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Annals of Gastroenterology 2020Curcumin, an active ingredient of the Indian herb turmeric (Curcuma longa), has shown promising anti-inflammatory properties. Studies of its potential benefits in...
BACKGROUND
Curcumin, an active ingredient of the Indian herb turmeric (Curcuma longa), has shown promising anti-inflammatory properties. Studies of its potential benefits in treating patients with ulcerative colitis (UC) are limited. We performed a systematic review and meta-analysis of human randomized placebo controlled trials to evaluate the efficacy of adjunctive therapy with curcumin in treating patients with UC.
METHODS
We conducted a search of several databases (from January 2000 to September 2018). A random-effects model was used for analysis. We assessed heterogeneity between study-specific estimates using the Cochran Q statistical test, 95% prediction interval (PI) and I statistics. The outcomes assessed were the pooled odds of clinical response and remission as well as the endoscopic response.
RESULTS
A total of 7 studies with 380 patients (curcumin n=188; placebo n=190) were included in the final analysis. The pooled odds ratio for clinical remission with curcumin use was 2.9 (95%CI 1.5-5.5, I=45, P=0.002), clinical response was 2.6 (95%CI 1.5-4.5, I=74%, P=0.001), and endoscopic response/remission was 2.3 (95%CI 1.2-4.6, I=35.5%, P=0.01).
CONCLUSIONS
Based on our study, combined mesalamine and curcumin therapy was associated with roughly threefold better odds of a clinical response compared to placebo, with minimal side effects. This response was statistically significant, albeit with heterogeneity, probably due to the different severity scoring indices, curcumin dosages and routes of drug delivery used.
PubMed: 31892798
DOI: 10.20524/aog.2019.0439 -
Journal of Gastroenterology and... May 2020Aminosalicylic acids are recognized to be the first-line treatment options for ulcerative colitis. Currently, the effectiveness of curcumin as an adjuvant treatment in... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Aminosalicylic acids are recognized to be the first-line treatment options for ulcerative colitis. Currently, the effectiveness of curcumin as an adjuvant treatment in ulcerative colitis has been investigated, which was still controversial. This study aimed to systematically review and meta-analyze the efficacy and safety of curcumin as an adjuvant treatment in ulcerative colitis.
METHODS
The PubMed, EMBASE, and Cochrane Library databases were searched from original to July 2019, and relevant randomized controlled clinical trials were enrolled and analyzed. The primary outcomes were clinical and endoscopic remission; meanwhile, the secondary outcomes were clinical and endoscopic improvement. Subgroup analyses of doses, delivery way, form, and intervention time of curcumin were also conducted.
RESULTS
Six randomized controlled clinical trials with a total of 349 patients were included. Eligible trials suggested that adjuvant curcumin treatment in ulcerative colitis was effective in inducing clinical remission (odds ratio [OR] = 5.18, 95% confidence interval [CI]: 1.84-14.56, P = 0.002), endoscopic remission (OR = 5.69, 95% CI: 1.28-25.27, P = 0.02), and endoscopic improvement (OR = 17.05, 95% CI: 1.30-233.00, P = 0.03), but not in clinical improvement (OR = 4.79, 95% CI: 1.02-22.43, P = 0.05). We can see the potential advantages in large dosage, topical enema, special drug form, and longer duration from the enrolled studies. There were no severe side effects reported.
CONCLUSIONS
Curcumin, as an adjuvant treatment of mesalamine, was proved to be effective and safe in ulcerative colitis. Better efficacy can be achieved with suitable dose, delivery way, formation, and intervention time, which needs further study to verify.
Topics: Chemotherapy, Adjuvant; Colitis, Ulcerative; Curcumin; Dosage Forms; Phytotherapy; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31696975
DOI: 10.1111/jgh.14911 -
British Journal of Clinical Pharmacology Oct 2019The comparative efficacy, safety and tolerability of budesonide-MMX and oral mesalamine in active, mild-to-moderate ulcerative colitis (UC) are unclear. We conducted a... (Comparative Study)
Comparative Study Meta-Analysis
AIMS
The comparative efficacy, safety and tolerability of budesonide-MMX and oral mesalamine in active, mild-to-moderate ulcerative colitis (UC) are unclear. We conducted a network meta-analysis to fill this evidence gap.
METHODS
We searched PubMed, Scopus, Embase, the Cochrane Library, clinical trial registries, regulatory agencies' websites and international conference proceedings, up to July 2018, to identify randomized controlled trials of adult patients with active, mild-to-moderate UC, comparing budesonide-MMX or mesalamine against placebo, or against each other, or different dosing strategies, for induction of remission. Two reviewers independently abstracted study data and outcomes, and assessed each trial's risk-of-bias.
RESULTS
We identified and synthesized evidence from 15 eligible trials including 4083 participants. Budesonide-MMX 9 mg/day and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission (OR = 0.97; 0.59-1.60), both showing superiority over placebo (OR = 2.68; 1.75-4.10, and OR = 2.75; 1.94-3.90, respectively). Furthermore, mesalamine >2.4 g/day was more efficacious than mesalamine 1.6-2.4 g/day (odds ratio = 1.27; 1.03-1.56). Secondary analyses showed that mesalamine >2.4 g/day ranks at the top among comparator treatments regarding safety (serious adverse events; surface under the cumulative ranking area [SUCRA] 79.2%) and tolerability (treatment discontinuations or withdrawals from the study due to adverse events; SUCRA 96.7%). There was no evidence of inconsistency, while heterogeneity between studies and risk of publication bias were low.
CONCLUSION
Budesonide-MMX and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission in active, mild-to-moderate UC; however, mesalamine >2.4 g/day showed better tolerability. Further high-quality research is warranted.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Colitis, Ulcerative; Delayed-Action Preparations; Glucocorticoids; Humans; Mesalamine; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 31269287
DOI: 10.1111/bcp.14051 -
The Cochrane Database of Systematic... Jun 2019Crohn's disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5-Aminosalicylates (5-ASAs) are locally acting,...
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.
Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Humans; Mesalamine; Quality of Life; Randomized Controlled Trials as Topic; Recurrence
PubMed: 31220875
DOI: 10.1002/14651858.CD008414.pub3 -
Revista de Gastroenterologia de Mexico... 2019Since the publication of the 2008 guidelines on the diagnosis and treatment of diverticular disease of the colon by the Asociación Mexicana de Gastroenterología,...
Since the publication of the 2008 guidelines on the diagnosis and treatment of diverticular disease of the colon by the Asociación Mexicana de Gastroenterología, significant advances have been made in the knowledge of that disease. A systematic review of articles published in the medical literature from January 2008 to July 2018 was carried out to revise and update the 2008 guidelines and provide new evidence-based recommendations. All high-quality articles in Spanish and English published within that time frame were included. The final versions of the 43 statements accepted in the three rounds of voting, utilizing the Delphi method, were written, and the quality of evidence and strength of the recommendations were established for each statement, utilizing the GRADE system. The present consensus contains new data on the definition, classification, epidemiology, pathophysiology, and risk factors of diverticular disease of the colon. Special emphasis is given to the usefulness of computed tomography and colonoscopy, as well as to the endoscopic methods for controlling bleeding. Outpatient treatment of uncomplicated diverticulitis is discussed, as well as the role of rifaximin and mesalazine in the management of complicated acute diverticulitis. Both its minimally invasive alternatives and surgical options are described, stressing their indications, limitations, and contraindications. The new statements provide guidelines based on updated scientific evidence. Each statement is discussed, and its quality of evidence and the strength of the recommendation are presented.
Topics: Colonic Diseases; Consensus; Delphi Technique; Diverticular Diseases; Diverticulitis; Guidelines as Topic; Humans; Mexico
PubMed: 31014749
DOI: 10.1016/j.rgmx.2019.01.002 -
Digestion 2020Oral 5-aminosalicylic acid (5-ASA, mesalazine) is the first choice therapeutic agent for treating mild-to-moderate ulcerative colitis (UC). Unfortunately a significant...
Does the 5-Aminosalicylate Concentration Correlate with the Efficacy of Oral 5-Aminosalicylate and Predict Response in Patients with Inflammatory Bowel Disease? A Systematic Review.
BACKGROUND
Oral 5-aminosalicylic acid (5-ASA, mesalazine) is the first choice therapeutic agent for treating mild-to-moderate ulcerative colitis (UC). Unfortunately a significant group of patients fail to respond. Therapeutic drug monitoring might help to maintain or induce remission by providing a tool for optimization of 5-ASA therapy. However, plasma and urine concentrations of 5-ASA reflect systemic uptake and are not useful to evaluate therapeutic effect.
OBJECTIVES
To explore if mucosal and faecal 5-ASA values correlate with disease activity and/or therapeutic effects in patients with inflammatory bowel disease, especially UC.
METHOD
We identified studies that analysed 5-ASA in faeces or mucosa of humans using an oral 5-ASA formulation, using PubMed and Embase.
RESULTS
In total, 39 studies (n = 939) were included, 27 on faecal 5-ASA, 9 on mucosal concentrations, and 3 on both faecal and mucosal values. We included 33 cross-sectional studies, 3 randomised clinical trials, 2 longitudinal cohorts and 1 randomized cross-over study. Mucosal 5-ASA concentrations in healthy subjects and patients on equivalent doses of 5-ASA were not found to differ remarkably. In the sub-analysis of mucosal 5-ASA concentrations in patients with active or quiescent UC, a higher concentration was seen during remission. Faecal concentrations were associated with 5-ASA doses but not with disease activity. Differences in faecal or mucosal 5-ASA values could not be ascribed to different 5-ASA formulations.
CONCLUSIONS
An increase of the mucosal 5-ASA concentrations was observed during remission in patients with UC. No clear relationship between the faecal 5-ASA excretion and the therapeutic efficacy was identified.
Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Colitis, Ulcerative; Colon; Drug Monitoring; Feces; Humans; Intestinal Mucosa; Mesalamine; Treatment Outcome
PubMed: 31013494
DOI: 10.1159/000499331 -
Medicine Apr 2019We aimed to conduct a meta-analysis to evaluate the efficacy and safety between once daily (OD) and twice daily (BD) regime dosing of mesalazine for mild-to-moderate... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to conduct a meta-analysis to evaluate the efficacy and safety between once daily (OD) and twice daily (BD) regime dosing of mesalazine for mild-to-moderate ulcerative colitis (UC).
METHODS
PubMed, Embase, the Cochrane library, and Web of Science from 1990 to November 2018 were investigated. We searched randomized controlled trials (RCTs) comparing OD with BD regime dosing of mesalazine for mild-to-moderate UC. The software Review Manager 5.3 was used to pool the risk ratio (RR) with a 95% confidence interval (CI).
RESULTS
Eight RCTs containing 3495 patients were identified. Regardless of induction of remission or maintenance of remission of UC, OD regime dosing of mesalazine was as effective as BD regime dosing in clinical and endoscopic remission and clinical remission. Also, no obvious difference was found between OD and BD regime dosing of mesalazine regardless of total adverse events, treatment-related adverse events or serious adverse events.
CONCLUSION
OD is as effective and safe as BD regime dosing of mesalazine for active UC.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Drug Administration Schedule; Humans; Mesalamine; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 30946380
DOI: 10.1097/MD.0000000000015113 -
Endocrine, Metabolic & Immune Disorders... 2019Sexual functions are sometimes adversely affected by the therapeutic drugs delivered for treating IBD. Much attention has been focused on pregnancy/sexual issues in... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Sexual functions are sometimes adversely affected by the therapeutic drugs delivered for treating IBD. Much attention has been focused on pregnancy/sexual issues in women. Relatively less attention has been poured in to address this issue in men. This systematic review assesses the drugs having potential detrimental effects on fertility in men.
METHODS
Three databases were searched by two researchers independently for potentially relevant publications between 1964 to 2015 and 249 papers were retrieved. Studies that dealt with sexual problems after IBD drugs administration were included in the purview of this review.
RESULTS
Fourteen studies with 327 human patients and 110 animals were analysed. Sulphasalazine treated patients had lower spermatozoa count, lower sperm motility and higher risk of oligospermia compared to mesalazine treated ones. Biologics seem to be safe to use while attempting to conceive however, proper clinical studies reporting male fertility problems in IBD patients are lacking. Azathioprine caused oligospermia but a meta-analytical approach was not possible due to heterogeneity in studies. Some animal studies showed methotrexate affects abnormal testis structure and spermatogenesis.
CONCLUSION
This study summarises the current literature and safety issues affecting fertility parameters in men and animals treated with IBD therapeutic drugs, which can further assist clinicians in better management of adult male IBD patients.
Topics: Animals; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infertility, Male; Inflammatory Bowel Diseases; Male; Sperm Motility; Spermatogenesis
PubMed: 30864530
DOI: 10.2174/1871530319666190313112110 -
World Journal of Gastroenterology Mar 2019Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease (MS-IBD). This study hypothesized that...
BACKGROUND
Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease (MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.
AIM
To investigate the effectiveness of conventional therapy for MS-IBD.
METHODS
A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Corticosteroids (prednisone, hydrocortisone, budesonide, prednisolone, dexamethasone), 5-aminosalicylic acid (5-ASA) derivatives (mesalazine and sulfasalazine) and immunosuppressants [azathioprine (AZA), methotrexate (MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine (6-MP)] were considered conventional therapy. The exclusion criteria were sample size below 50; narrative reviews; specific subpopulations (., pregnant women, comorbidities); studies on postoperative IBD; and languages other than English, Spanish, French or Portuguese. The primary outcome measures were clinical remission (induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.
RESULTS
The search strategy identified 1995 citations, of which 27 were considered eligible (7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected (AZA and 6-MP showed no advantage over placebo, MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials (RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing, one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.
CONCLUSION
High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Colon; Crohn Disease; Feces; Glucocorticoids; Humans; Immunosuppressive Agents; Intestinal Mucosa; Leukocyte L1 Antigen Complex; Remission Induction; Severity of Illness Index; Treatment Outcome
PubMed: 30863001
DOI: 10.3748/wjg.v25.i9.1142 -
Minerva Gastroenterologica E Dietologica Jun 2019Rectal inflammation is the principal risk factor for the development of perianal fistulizing Crohn's disease. However, no topical therapy direct to rectal healing is...
INTRODUCTION
Rectal inflammation is the principal risk factor for the development of perianal fistulizing Crohn's disease. However, no topical therapy direct to rectal healing is discussed in European' guidelines. The aim of this systematic review was to evaluate the role of topical therapy in healing the rectal inflammation in Crohn's disease.
EVIDENCE ACQUISITION
A MEDLINE search of all studies published in English until December 2018 was conducted. Articles were identified using the strings "Crohn's disease and topical therapy" or "perianal Crohn's disease and topical therapy."
EVIDENCE SYNTHESIS
Contradictory results about the efficacy of topical metronidazole were present. No benefit from topical tacrolimus use was demonstrated. Mesalazine suppositories induced and maintained remission of rectal inflammation in 50% of patients with rectal Crohn's disease. Few data were available about the role of local therapy for the fistulous tract in Crohn's disease. Local mesenchymal stem cells therapy could be a promising new approach.
CONCLUSIONS
Due to the disappoint success rate of current strategy in perianal fistulizing Crohn's disease, the role of rectal inflammation as a causative factor and the fair success rate of topical therapy with mesalazine suppositories in the healing of rectal inflammation without relevant side effects, more studies are advisable in this field.
Topics: Administration, Topical; Anus Diseases; Crohn Disease; Humans; Intestinal Fistula
PubMed: 30759975
DOI: 10.23736/S1121-421X.19.02565-0