Expression of MMP-2, MMP-7, MMP-9, and TIMP-1 by Inflamed Mucosa in the Initial Diagnosis of Ulcerative Colitis as a Response Marker for Conventional Medical Treatment.

INTRODUCTION: Experimental and clinical data involve matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis of inflammatory bowel diseases. However, the impact of MMPs/TIMPs expression by inflamed mucosa on medical response therapy has scarcely been investigated. METHODS: The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 was determined by immunohistochemical analysis in inflamed mucosa samples at diagnosis in 82 patients with ulcerative colitis (UC; 22 never-treated with corticosteroids, 28 nonresponders, and 32 responders to corticosteroid therapy) and 15 patients with acute diverticulitis (AD). The global expression (score value) of each factor was analyzed by computer-generated image analysis. RESULTS: UC samples showed higher MMP-2 and MMP-9 expression but lower TIMP-1 expression than the AD samples (p < 0.0001, for all). High MMP-9 and TIMP-1 scores were significantly associated with no need for corticosteroid treatment (p < 0.001 and p = 0.017, respectively); whereas higher score in the MMP-7 expression was significantly associated with nonresponse to corticosteroid therapy (p = 0.037). In addition, in this latter UC subgroup, MMP-7 correlated positively with the younger age of the patients and with the extension of the disease (p = 0.030 and p = 0.010, respectively). CONCLUSION: Our results suggest the relevance of MMPs and TIMPs for predicting treatment response to both 5-aminosalicylates and corticosteroids in UC.

Vedolizumab does not increase risk of clostridium difficile infection in patients with inflammatory bowel disease using vedolizumab: A retrospective cohort study.

Introduction: Several studies have shown increased incidence, recurrence, and severity of Clostridium difficile infection (CDI) over the last decade. Patients with inflammatory bowel disease (IBD) who develop CDI are more prone to morbidity and mortality than CDI in patients without IBD. This study seeks to evaluate whether IBD patients who use vedolizumab are at increased risk of CDI compared to IBD patients using other therapies. Methods: This was a retrospective cohort study, and 684 patients with confirmed IBD (228 on vedolizumab, 228 on anti-TNF, and 228 on 5- Aminosalicylates acid therapy) were enrolled from January 2009 to August 2019 at a tertiary referral IBD center at McMaster University Medical Centre (MUMC) in Hamilton, Ontario, Canada. The primary outcome was time to the development of CDI in IBD patients using different therapies. Secondary outcomes included rates of CDI and the association between baseline variables and risk of CDI. A Cox proportional hazards (PH) model was used to evaluate baseline factors and development of CDI. Result: There was no difference in time to CDI between the three treatment groups (log rank p-value 0.37). CDI occurred in 16 patients (2.3%), specifically four patients (1.75%) in the vedolizumab group, four patients (1.75%) in the anti-TNF group, and eight patients (3.5%) in the 5-ASA group. The Cox PH model found current smoking, older age, and concomitant immunomodulator use as risk factors for CDI, after adjustment for other covariates. Vedolizumab was not associated with increased risk of CDI in the model. Conclusion: Biologic therapy with vedolizumab or anti-TNF did not impact risk of CDI. Risk factors for CDI in IBD patients included smoking, older age at the onset of medication, and immunomodulator therapy. Clinicians should have high degree of suspicion for CDI in IBD patients presenting with diarrhea, particularly in those with risk factors identified in this study.

Effects of 5-aminosalicylates or thiopurines on the progression of low-grade dysplasia in patients with inflammatory bowel disease: a systematic review and meta-analysis.

PURPOSE: Although 5-aminosalicylates and thiopurines may have an antineoplastic effect on colorectal neoplasia in patients with inflammatory bowel disease (IBD), their impact on the progression of low-grade dysplasia (LGD) in IBD is uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate whether 5-aminosalicylates or thiopurines can protect against the progression of LGD in patients with IBD. METHODS: Systematic searches of PubMed, EMBASE, Cochrane Library databases, and major conference proceedings were conducted to identify all eligible studies through March 2020. Data were pooled using a random effects model. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Five studies comprising 776 IBD patients with LGD were included. Overall, 5-aminosalicylates (Hazard ratio (HR) = 0.91, 95% confidence interval (CI) 0.55-1.51) and thiopurines (HR = 0.64, 95% CI 0.23-1.79) did not significantly reduce the risk of advanced colorectal neoplasia (high-grade dysplasia/cancer) in IBD patients with LGD. Moreover, the effects of 5-aminosalicylates or thiopurines on risk of advanced colorectal neoplasia in IBD patients with LGD were not significant by different primary sclerosing cholangitis status, study quality, sample size, and IBD type. CONCLUSIONS: In this study, we did not find a significant protective effect of 5-aminosalicylates or thiopurines on the progression of LGD in patients with IBD.

[Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management].

Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.

Inflammatory Bowel Diseases Are Associated With an Increased Risk for Chronic Kidney Disease, Which Decreases With Age.

BACKGROUND & AIMS: It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR). METHODS: We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model. RESULTS: After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m2; 95% CI, 0.16-0.48). CONCLUSIONS: In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR.

Stopping 5-aminosalicylates in patients with ulcerative colitis starting biologic therapy does not increase the risk of adverse clinical outcomes: analysis of two nationwide population-based cohorts.

OBJECTIVE: The benefit of continuing 5-aminosalicylate (5-ASA) in patients with ulcerative colitis (UC) who initiate anti-tumour necrosis factor-alpha (anti-TNF) biologics is unknown. We aimed to compare clinical outcomes in patients with UC already on 5-ASA who started anti-TNF and then either stopped or continued 5-ASA. DESIGN: Our primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, UC-related hospitalisation or surgery. We used two national databases: the United States (US) Truven MarketScan health claims database and the Danish health registers. Patients with UC who started anti-TNF after having been on oral 5-ASA for at least 90 days were included. Patients were classified as stopping 5-ASA if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors and healthcare utilisation. Adjusted HRs (aHR) with 95% CI are reported comparing stopping 5-ASA with continuing 5-ASA. RESULTS: A total of 3589 patients with UC were included (2890 US and 699 Denmark). Stopping 5-ASA after initiating anti-TNF was not associated with an increased risk of adverse clinical events in the U.S. cohort (aHR 1.04; 95% CI 0.90 to 1.21, p=0.57) nor in the Danish cohort (aHR 1.09; 95% CI 0.80 to 1.49, p=0.60). Results were similar in sensitivity analyses investigating concomitant immunomodulator use and duration of 5-ASA treatment before initiating anti-TNF. CONCLUSION: In two national databases, stopping 5-ASA in patients with UC starting anti-TNF therapy did not increase the risk of adverse clinical events. These results should be validated in a prospective clinical trial.

The impact of 5-aminosalicylates on the efficacy of mesenchymal stem cell therapy in a murine model of ulcerative colitis.

Inflammatory bowel disease (IBD) is distinguished by persistent immune-mediated inflammation of the gastrointestinal tract. Previous experimental investigations have shown encouraging outcomes for the use of mesenchymal stem cell (MSC)-based therapy in the treatment of IBD. However, as a primary medication for IBD patients, there is limited information regarding the potential interaction between 5-aminosalicylates (5-ASA) and MSCs. In this present study, we employed the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model to examine the influence of a combination of MSCs and 5-ASA on the development of UC. The mice were subjected to weight measurement, DAI scoring, assessment of calprotectin expression, and collection of colons for histological examination. The findings revealed that both 5-ASA and MSCs have demonstrated efficacy in the treatment of UC. However, it is noteworthy that 5-ASA exhibits a quicker onset of action, while MSCs demonstrate more advantageous and enduring therapeutic effects. Additionally, the combination of 5-ASA and MSC treatment shows a less favorable efficacy compared to the MSCs alone group. Moreover, our study conducted in vitro revealed that 5-ASA could promote MSC migration, but it could also inhibit MSC proliferation, induce apoptosis, overexpress inflammatory factors (IL-2, IL-12P70, and TNF-α), and reduce the expression of PD-L1 and PD-L2. Furthermore, a significant decrease in the viability of MSCs within the colon was observed as a result of 5-ASA induction. These findings collectively indicate that the use of 5-ASA has the potential to interfere with the therapeutic efficacy of MSC transplantation for the treatment of IBD.

Risk Factors for COVID-19 in Inflammatory Bowel Disease: A National, ENEIDA-Based Case-Control Study (COVID-19-EII).

(1) Scant information is available concerning the characteristics that may favour the acquisition of COVID-19 in patients with inflammatory bowel disease (IBD). Therefore, the aim of this study was to assess these differences between infected and noninfected patients with IBD. (2) This nationwide case−control study evaluated patients with inflammatory bowel disease with COVID-19 (cases) and without COVID-19 (controls) during the period March−July 2020 included in the ENEIDA of GETECCU. (3) A total of 496 cases and 964 controls from 73 Spanish centres were included. No differences were found in the basal characteristics between cases and controls. Cases had higher comorbidity Charlson scores (24% vs. 19%; p = 0.02) and occupational risk (28% vs. 10.5%; p < 0.0001) more frequently than did controls. Lockdown was the only protective measure against COVID-19 (50% vs. 70%; p < 0.0001). No differences were found in the use of systemic steroids, immunosuppressants or biologics between cases and controls. Cases were more often treated with 5-aminosalicylates (42% vs. 34%; p = 0.003). Having a moderate Charlson score (OR: 2.7; 95%CI: 1.3−5.9), occupational risk (OR: 2.9; 95%CI: 1.8−4.4) and the use of 5-aminosalicylates (OR: 1.7; 95%CI: 1.2−2.5) were factors for COVID-19. The strict lockdown was the only protective factor (OR: 0.1; 95%CI: 0.09−0.2). (4) Comorbidities and occupational exposure are the most relevant factors for COVID-19 in patients with IBD. The risk of COVID-19 seems not to be increased by immunosuppressants or biologics, with a potential effect of 5-aminosalicylates, which should be investigated further and interpreted with caution.

When disease extent is not always a key parameter: Management of refractory ulcerative proctitis.

BACKGROUND: Patients with ulcerative proctitis represent a sub-group of ulcerative colitis patients with specific characteristics. Disease-related symptoms, endoscopic findings and patient's personality perspectives create a difficult-to-assess condition in certain cases. OBJECTIVES: To summarize available evidence on the management of refractory ulcerative proctitis and provide insights in treatment options. RESULTS: /Conclusion: Topical therapy plays a central role due to the location of the disease. However, well-established treatment options may become exhausted in a considerable proportion of ulcerative proctitis patients, indicating the need to advance to more potent therapies in order to induce and maintain clinical response and remission in these refractory cases. Systemic corticosteroids, thiopurines, calcineurin inhibitors, biologic agents and small molecules have all been tested with variable success rates. Investigational interventions as well as surgical procedures are kept as the ultimate resort in multi-treatment resistant cases. Identifying early prognostic factors that herald a disabling disease progression will help in optimizing treatment and avoiding surgery.

The safe use of inflammatory bowel disease therapies during the COVID-19 pandemic.

Background: Patients with inflammatory bowel disease (IBD) often require the use of immunosuppressant medications that increase infection risk, leading to concerns over the safe use of IBD medications during the Coronavirus 19 (COVID-19) pandemic. Objectives: To summarize available evidence on the safety and appropriate use of IBD medications during the COVID-19 pandemic, particularly in regard to risk of severe COVID-19 outcomes such as hospitalization, respiratory failure, or death for patients on IBD therapeutics. Conclusions: The majority of IBD medications are safe to continue during the COVID-19 pandemic, with a few notable exceptions. Patients with IBD who do not have COVID-19 should continue their prescribed IBD therapies, although steroids are associated with severe COVID-19 outcomes and should be weaned when possible. Corticosteroids should be tapered and discontinued when possible in patients with IBD who test positive for COVID-19 as well. Patients with IBD who test positive for COVID-19 should hold biologics, thiopurines, methotrexate, and tofacitinib for at least 2 weeks, and those who have symptoms should not restart these medications until symptom resolution. During the COVID-19 pandemic, all patients with IBD should continue to follow public health guidance including social distancing, masking, and COVID-19 vaccination recommendations.

Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-analysis.

BACKGROUND: 5-Aminosalicylates [5-ASAs] are the mainstay of treatment for ulcerative colitis [UC]. The optimum preparation, dose, and route of administration for UC remain unclear. We conducted a network meta-analysis to examine this issue. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to December 2020. We included randomised controlled trials [RCTs] comparing oral, topical, or combined oral and topical 5-ASAs, with each other or placebo for induction of remission or prevention of relapse of UC. Results were reported as pooled relative risks [RRs] with 95% confidence intervals [CIs] to summarise effect of each comparison tested, with treatments ranked according to P-score. RESULTS: We identified 40 RCTs for induction of remission and 23 for prevention of relapse. Topical mesalazine [P-score 0.99], or oral and topical mesalazine combined [P-score 0.87] ranked first and second for clinical and endoscopic remission combined. Combined therapy ranked first in trials where ≥50% of patients had left-sided/extensive disease, and topical mesalazine first in trials where ≥50% of patients had proctitis/proctosigmoiditis. High-dose [≥3.3 g/day] oral mesalazine ranked third in most analyses, with the most trials and most patients. For relapse of disease activity, combined therapy and high-dose oral mesalazine ranked first and second, with topical mesalazine third. 5-ASAs were safe and well tolerated, regardless of regimen. CONCLUSIONS: Our results support previous evidence; however, higher doses of oral mesalazine had more evidence for induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should better establish the role of combined therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse.

The use of 5-aminosalicylate for patients with Crohn's disease in a prospective European inception cohort with 5 years follow-up - an Epi-IBD study.

BACKGROUND: The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice. AIMS: The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease. METHODS: In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists. RESULTS: Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%)). CONCLUSION: In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.

Solving the questions regarding 5-aminosalitylate formulation in the treatment of ulcerative colitis.

5-aminosalicylate is a fundamental treatment for patients with ulcerative colitis with mild-to-moderate disease; however, evidence for 5-aminosalicylate treatment is unclear in some situations. This review discusses the clinical guidelines and previous studies, and highlights the following points: (1) Although rectal 5-aminosalicylate is effective for proctitis, physicians should endeavor to reduce patient's distress when administering suppositories or enema as the first-line therapy. It should be clarified whether oral 5-aminosalicylate alone with a drug delivery system that allows higher 5-aminosalicylate concentrations to reach the distal colon would be as effective as rectal 5-aminosalicylate therapy. (2) There has been no direct evidence demonstrating the clinical efficacy of switching the 5-aminosalicylate treatment to other 5-aminosalicylate formulations. However, switching to a different 5-aminosalicylate formulation may be indicated if clinical symptoms are not progressive. (3) Several studies have shown that colonic mucosal 5-aminosalicylate concentration correlates with clinical and endoscopic severity; however, it is unclear whether a high 5-aminosalicylate concentration has therapeutic efficacy. (4) The maximum dose of 5-aminosalicylate is necessary for patients with risk factors for recurrence or hospitalization. (5) Optimization of 5-aminosalicylate dosage may be indicated even for quiescent patients with ulcerative colitis if mucosal healing is not obtained, and if patients have multiple risk factors for recurrence. (6) Furthermore, the discontinuation of 5-aminosalicylate is acceptable when biologics are used. Because there are many "old studies" providing evidence for 5-aminosalicylate formulations, more clinical studies are needed to establish new evidence.

Reviewing the Risk of Colorectal Cancer in Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis.

The presence of concomitant primary sclerosing cholangitis (PSC) with inflammatory bowel disease (IBD) represents a distinct disease phenotype that carries a higher risk of colorectal cancer (CRC) than the average IBD patient. Given that liver transplantation (LT) is the only treatment that offers a survival benefit in PSC patients with hepatic dysfunction, management decisions in IBD patients' post-LT for PSC are frequently encountered. One such consideration is the risk of CRC in this immunosuppressed cohort. With most studies showing an increased risk of CRC post-LT in these IBD patients, a closer look at the associated risk factors of CRC and the adopted surveillance strategies in this subset of patients is warranted. Low-dose ursodeoxycholic acid has shown a potential chemopreventive effect in PSC-IBD patients pre-LT; however, a favorable effect remains to be seen in post-LT group. Also, further studies are necessary to assess the benefit of 5 aminosalicylate therapy. Annual surveillance colonoscopy in the post-LT period is recommended for PSC-IBD patients subset given their high risk for CRC.

Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis: A global survey of physicians' practice.

AIM: To examine treatment decisions of gastroenterologists regarding the choice of prescribing 5-aminosalycilates (5ASA) with corticosteroids (CS) versus corticosteroids alone for patients with active ulcerative colitis (UC). METHODS: A cross-sectional questionnaire exploring physicians' attitude toward 5ASA + CS combination therapy vs CS alone was developed and validated. The questionnaire was distributed to gastroenterology experts in twelve countries in five continents. Respondents' agreement with stated treatment choices were assessed by standardized Likert scale. Background professional characteristics of respondents were analyzed for correlation with responses. RESULTS: Six hundred and sixty-four questionnaires were distributed and 349 received (52.6% response rate). Of 340 eligible respondents, 221 (65%) would continue 5ASA in a patient hospitalized for intravenous CS treatment due to a moderate-severe UC flare, while 108 (32%) would stop the 5ASA (P < 0.001), and 11 (3%) are undecided. Similarly, 62% would continue 5ASA in an out-patient starting oral CS. However, only 140/340 (41%) would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + CS were positively associated with the decision to continue 5ASA with CS. CONCLUSION: Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + CS for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Chemoprevention of colorectal cancer in inflammatory bowel disease.

INTRODUCTION: Patients with inflammatory bowel disease are at an increased risk of colorectal cancer when compared to the general population. Chronic inflammation is thought to be the underlying cause, and medications that reduce inflammation have the potential to reduce the risk of colorectal cancer. Areas covered: After conducting a PubMed search for relevant literature, we examined several classes of medications that have been studied as potential chemopreventive agents. These include 5-aminosalicylates, thiopurines, tumor necrosis factor antagonists, ursodeoxycholic acid, NSAIDs, and statins. Expert commentary: While each class of medications has some data to support its use in chemoprevention, the majority of the evidence in each case argues against the routine use of these medications solely for a chemopreventive benefit.

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease.

BACKGROUND AND AIMS: A number of agents have been evaluated in clinical trials to reduce the risk of postoperative recurrence in Crohn's disease (CD). The aim of this study was to compare the efficacy of 5-aminosalicylates, immunomodulators and biologics for postoperative prophylaxis of CD recurrence by using a network meta-analytical approach. METHODS: PubMed, Embase, and Cochrane Library were searched (update to November 2013) to identify randomized placebo-controlled, or head-to-head trials among the three drug classes for prevention of postoperative CD relapse. The primary endpoint for efficacy was endoscopic recurrence, and the secondary outcomes were clinical recurrence and adverse events. We conducted a Bayesian network meta-analysis with a mixed treatment comparisons to combine both direct and indirect evidences. RESULTS: Fifteen trials involving 1507 patients were included in this analysis. Biological agents were associated with a large and significant reduction of both endoscopic and clinical recurrence compared with placebo, 5-aminosalicylates, or immunomodulators. Immunomodulators showed greater efficacy in terms of endoscopic and clinical recurrence prophylaxis compared with 5-aminosalicylates or placebo, but with higher incidence of adverse events. 5-aminosalicylates were superior to placebo for prevention of clinical recurrence, without increasing the rate of side effect. CONCLUSIONS: 5-aminosalicylates, immunomodulators, and biologics are more efficacious than placebo for postoperative CD prevention. Biologics are found to be the most effective medications to prevent CD recurrence.

Ulcerative proctitis: an update on the pharmacotherapy and management.

INTRODUCTION: Ulcerative colitis (UC) presents as proctitis in approximately a quarter of the patients. It may progress into left-sided or extensive colitis in up to 50% of cases upon long-term follow-up. AREAS COVERED: Currently available data on ulcerative proctitis are summarized and critically reviewed. Extensive literature search (MEDLINE) was performed to identify relevant articles up to March 2014. EXPERT OPINION: The short-term goal of the treatment in UC is to induce remission, whereas long-term goals are to maintain remission and prevent disease progression. Topically administered 5-aminosalicylates (5-ASA) and corticosteroids are effective in the treatment of proctitis, although they seem to be underused in everyday practice. Locally administered 5-ASA preparations are more effective than oral compounds. The combination of topical and oral 5-ASA and steroids should be considered for escalation of treatment. Refractory patients should be re-evaluated to exclude for compliance failures, infections or proximal disease extent. True refractory or steroid-dependent patients may require immunomodulators or biological therapy. Alternative medicine can be used complementarily, while experimental approaches are reserved for patients failing conventional medication. Proctocolectomy may be the last resort of treatment. Upon long-term, 5-ASA maintenance treatment is indicated in all UC cases to prevent relapse and disease progression.

Presence of phthalates in gastrointestinal medications: is there a hidden danger?

Pharmaceutical companies that produce gastrointestinal (GI) medications often utilize phthalates for their ability to localize medication release. Commonly prescribed GI medications that may utilize phthalates are 5-Aminosalicylates, proton pump inhibitors, and pancreatic enzymes. Our understanding of the cumulative health effects of phthalates from medications remains unclear, and there is increasing evidence that phthalates are not harmless. Experimental studies in animals have shown that phthalates, specifically dibutyl phthalate and Di-(2-ethyl-hexyl) phthalate, have the potential to alter and/or inhibit reproductive biology and in utero development. Despite the lack of definitive human data, many cohort and cross-sectional studies demonstrate concerning associations between phthalates and poor health status, specifically developmental problems. Longitudinal studies and studies with larger sample sizes are required to determine whether phthalates actually cause negative health consequences. It is also important that physicians regularly review and discuss with patients the medicinal ingredients in their medications and supplements, specifically in pregnant woman with inflammatory bowel disease.