The Use of Sulfasalazine in Atrophie Blanche

Atrophie blanche can be a chronic condition for which there is no satisfactory treatment. Two patients with atrophie blanche who had not responded to various therapeutic modalities were given a trial of sulfasalazine 1 g three times daily. The ulcers healed within 3 months in both cases. In view of these positive results, patients should be treated with sulfasalazine to determine the efficacy of this drug in atrophie blanche.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65527/1/j.1365-4362.1990.tb02594.x.pd

Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis

Background Basolateral K+ channels hyperpolarize colonocytes to ensure Na+ (and thus water) absorption. Small conductance basolateral (KCNQ1/KCNE3) K+ channels have never been evaluated in human colon. We therefore evaluated KCNQ1/KCNE3 channels in distal colonic crypts obtained from normal and active ulcerative colitis (UC) patients. Methods KCNQ1 and KCNE3 mRNA levels were determined by qPCR, and KCNQ1/KCNE3 channel activity in normal and UC crypts, and the effects of forskolin (activator of adenylate cyclase) and UC-related proinflammatory cytokines on normal crypts, studied by patch clamp recording. Results Whereas KCNQ1 and KCNE3 mRNA expression was similar in normal and UC crypts, single 6.8 pS channels were seen in 36% of basolateral patches in normal crypts, and to an even greater extent (74% of patches, P < 0.001) in UC crypts, with two or more channels per patch. Channel activity was 10-fold higher (P < 0.001) in UC crypts, with a greater contribution to basolateral conductance (5.85 ± 0.62 mS cm−2) than in controls (0.28 ± 0.04 mS cm−2, P < 0.001). In control crypts, forskolin and thromboxane A2 stimulated channel activity 30-fold and 10-fold respectively, while PGE2, IL-1β, and LTD4 had no effect. Conclusions KCNQ1/KCNE3 channels make only a small contribution to basolateral conductance in normal colonic crypts, with increased channel activity in UC appearing insufficient to prevent colonic cell depolarization in this disease. This supports the proposal that defective Na+ absorption rather than enhanced Cl− secretion, is the dominant pathophysiological mechanism of diarrhea in UC

Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease

Background Crohn’s disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5‐Aminosalicylates (5‐ASAs) are locally acting, anti‐inflammatory compounds that reduce inflammation of the colonic mucosa with release profiles that vary among various commercially available formulations. This updated Cochrane review summarizes current evidence on the use of 5‐ASA formulations for maintenance of surgically‐induced remission in CD. Objectives To assess the efficacy and safety of 5‐ASA agents for the maintenance of surgically‐induced remission in CD. Search methods We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register from inception to 16 July 2018. We also searched references, conference abstracts, and trials registers. Selection criteria Randomised controlled trials (RCTs) that included participants with CD in remission following surgery and compared 5‐ASAs to no treatment, placebo or any other active intervention with duration of at least three months were considered for inclusion. Data collection and analysis We used standard methodological procedures expected by Cochrane. The primary outcome was clinical relapse. Secondary outcomes included endoscopic recurrence, radiologic and surgical relapse, adverse events, serious adverse events and withdrawal due to adverse events. Main results Fourteen RCTs (1867 participants) were included in the review. Participants (15 to 70 years) were recruited from gastroenterology hospitals and medical clinics in Europe and North America and followed up between 3 and 72 months. The risk of bias was assessed as 'low' in one study, 'unclear' in seven and as 'high' in six. At 12 months, 36% (20/55) of participants in the 5‐ASA group experienced clinical relapse compared to 51% (28/55) in the no treatment control group (RR 0.71, 95% CI 0.46 to 1.10; low certainty evidence). Moderate certainty evidence suggests that 5‐ASAs are more effective for preventing clinical relapse than placebo. During a follow‐up period of 12 to 72 months, 36% (131/361) of 5‐ASA participants relapsed compared to 43% (160/369) of placebo participants (RR 0.83, 95% CI 0.72 to 0.96; I² = 0%; moderate certainty evidence). At 12 months, 17% (17/101) of the 4 g/day mesalamine group relapsed compared to 26% (27/105) of the 2.4 g/day group (RR 0.65, 95% CI 0.38 to 1.13; moderate certainty evidence). There was no evidence of a difference in clinical relapse rates when 5‐ASA compounds were compared to purine antimetabolites. At 24 months, 61% (103/170) of mesalamine participants relapsed compared to 67% (119/177) of azathioprine participants (RR 0.90, 95% CI 0.76 to 1.07; I² = 28%; low certainty evidence). During 24 months, 50% (9/18) of 5‐ASA participants had clinical relapse compared to 13% (2/16) of adalimumab participants (RR 4.0, 95% CI 1.01 to 15.84; low certainty evidence). The effects of sulphasalazine compared to placebo on clinical relapse rate is uncertain. After 18 to 36 months, 66% (95/143) of participants treated with sulphasalazine relapsed compared to 71% (110/155) in the placebo group (RR 0.88, 95% CI 0.56 to 1.38; I² = 38%; low certainty evidence). The effect of 5‐ASA drugs on safety was uncertain. During 24 months follow‐up, 4% (2/55) of 5‐ASA participants experienced adverse events compared to none (0/55) in the no treatment control group (RR 5.00, 95% CI 0.25 to 101.81; very low certainty evidence). An equal proportion of 5‐ASA participants (10%; 23/241) and placebo (9%; 20/225) groups experienced an adverse event during a follow‐up of 3 to 72 months (RR 1.07, 95% CI 0.60 to 1.91; I² = 0%; low certainty evidence). Adverse event rates were similar in the 5‐ASA and purine analogues groups. However, serious adverse events and withdrawals due to adverse events were more common in participants who received purine analogues than 5‐ASA. At 52 weeks to 24 months, 52% (107/207) of 5‐ASA participants had an adverse event compared to 47% (102/218) of purine analogue participants (RR 1.11, 95% CI 0.97 to 1.27, I² = 0%; low certainty evidence). Four per cent (6/152) of 5‐ASA participants had a serious adverse event compared to 17% (27/159) of purine analogue participants (RR 0.30, 95% CI 0.11 to 0.80; very low certainty evidence). Eight per cent (17/207) of 5‐ASA participants withdrew due to an adverse event compared to 19% (42/218) of purine analogue participants (RR 0.48, 95% CI 0.28 to 0.83; low certainty evidence). Adverse event rates were similar in high and low dose mesalamine participants. After 12 months, 2% (2/101) of 4 g/day mesalamine participants had an adverse event compared to 2% (2/105) of 2.4 g/day participants (RR 1.04, 95% CI 0.15 to 7.24; low certainty evidence). The proportion of participants who experienced adverse events over a 24 month follow‐up in the mesalamine group was 78% (14/18) compared to 69% (11/16) of adalimumab participants (RR 1.13, 95% CI 0.75 to 1.71; very low certainty evidence). None (0/32) of the sulphasalazine participants had an adverse event at 18 months follow‐up compared to 3% (1/34) of the placebo group (RR 0.35, 95% CI 0.01 to 8.38; very low certainty evidence). Commonly reported adverse events in the included studies were diarrhoea, nausea, increased liver function tests, pancreatitis, and abdominal pain. Authors' conclusions 5‐ASA preparations are superior to placebo for the maintenance of surgically‐induced clinical remission in patients with CD (moderate certainty). The number needed to treat to prevent one relapse was 13 patients. The evidence for endoscopic remission is uncertain. The sulphasalazine class of 5‐ASA agents failed to demonstrate superiority against placebo, 5‐ASAs failed to demonstrate superiority compared to no treatment (very low and low certainty). The efficacy of two different doses of the same 5‐ASA and the efficacy of 5‐ASA compared to purine antimetabolites (azathioprine or 6‐mercaptopurine) in maintaining surgically‐induced remission of CD remains unclear. However, purine analogues lead to more serious adverse events and discontinuation due to adverse events. There is a low certainty that 5‐ASA is inferior for maintaining surgically‐induced remission of CD compared to biologics (anti TNF‐ɑ). 5‐ASA formulations appear to be safe with no difference in the occurrence of adverse events or withdrawal when compared with placebo, no treatment or biologics

Incretin-based therapies and risk of pancreatic cancer in patients with type 2 diabetes : A meta-analysis of randomized controlled trials

Aims: To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM). Materials and Methods: For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of >= 52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate. Results: A total of 33 studies (n = 79971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for >= 104 weeks, 84 pancreatic cancer events were identified in 59919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95). Conclusions: Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for 104 weeks.Peer reviewe

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity.

Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β(-/-)), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity

Drug therapy in peptic ulcer disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28099/1/0000546.pd