Real-world clinical and endoscopic outcomes after one year tofacitinib treatment in ulcerative colitis.

OBJECTIVE: Tofacitinib, an oral Janus kinase inhibitor, is approved for the treatment of moderate to severe ulcerative colitis (UC). We evaluated clinical and endoscopic efficacy, safety and drug survival of tofacitinib up to one year in a real-world cohort. METHODS: In this retrospective cohort study, 36 UC patients were included who received tofacitinib. The primary outcome was combined with steroid-free clinical remission [Simple Clinical Colitis Activity Index (SCCAI) ≤2] and endoscopic improvement (Mayo score ≤1) at 52 weeks. Secondary outcomes included clinical (SCCAI drop ≥3) and endoscopic response (Mayo score drop ≥1), biochemical remission [fecal calprotectin (FC) ≤150 mg/kg and C-reactive protein ≤5 mg/L), safety and drug survival. RESULTS: Median disease duration was 7 (3-14) years and 89 and 42% of patients failed prior anti-tumor necrosis factor (anti-TNF) and vedolizumab treatment, respectively. Combined corticosteroid-free clinical remission and endoscopic improvement were observed in 8/36 patients (22%), 6/35 (17%) and 12/31 (39%), at 16, 36 and 52 weeks, respectively. Corresponding combined clinical and endoscopic response rates were 15/36 (42%), 12/35 (34%), 15/31 (48%) and biochemical remission rates were 11/33 (33%), 10/32 (31%) and 10/29 (34%). Nine infections (two herpes zoster) led to dose reduction or (temporary) drug withdrawal. Permanent withdrawal occurred in 14/36 patients (33%) after a median duration of 9 (5-30) weeks. Drug survival at 1 year was 60%. Patients that failed anti-TNF were less likely to discontinue tofacitinib treatment early compared to patients without prior anti-TNF use (hazard ratio 0.20, 95% confidence interval 0.06-0.65). CONCLUSION: In a refractory UC population, combined steroid-free clinical remission and endoscopic improvement were found in 39% of patients at 1 year.

High Disease Burden Drives Indirect Costs in Employed Inflammatory Bowel Disease Patients: The WORK-IBD Study.

BACKGROUND: Work productivity (WP) loss includes absence from work (absenteeism) and productivity loss while working (presenteeism), which leads to high indirect costs in inflammatory bowel disease (IBD). Prior health economic analyses predominantly focused on absenteeism. Here we focus on presenteeism and assess predictors of WP loss, fatigue, and reduced health-related quality of life (HRQL). METHODS: Employed IBD patients completed the following surveys: Work Productivity and Activity Impairment, Multidimensional Fatigue Inventory, and Short Inflammatory Bowel Disease Questionnaire. Predictors were assessed using uni- and multivariable regression analyses. Annual costs were calculated using percentages of WP loss, hourly wages, and contract hours. RESULTS: Out of 1590 invited patients, 768 (48%) responded and 510 (32%) were included. Absenteeism, presenteeism, and overall WP loss were reported by 94 (18%), 257 (50%), and 269 (53%) patients, respectively, resulting in mean (SD) annual costs of €1738 (5505), €5478 (8629), and €6597 (9987), respectively. Disease activity and active perianal disease were predictors of WP loss (odds ratio [OR] = 6.6; 95% confidence interval [CI], 3.6-12.1); OR = 3.7; 95% CI, 1.5-8.7). Disease activity and arthralgia were associated with fatigue (OR = 3.6; 95% CI, 1.9-6.8; OR = 1.8; 95% CI, 1.0-3.3)) and reduced HRQL (OR = 10.3; 95% CI, 5.9-17.9; OR = 2.3; 95 % CI, 1.4-3.8). Fatigue was the main reason for absenteeism (56%) and presenteeism (70%). Fatigue and reduced HRQL led to increased costs compared with absence of fatigue and normal HRQL (mean difference = €6630; 95% CI, €4977-€8283, P < 0.01; mean difference = €9575; 95% CI, €7767-€11,384, P < 0.01). CONCLUSIONS: Disease activity and disease burden lead to WP loss in approximately half of the employed IBD population, driving indirect costs. Fatigue is the most important reason for WP loss.

Decreasing Trends in Intestinal Resection and Re-Resection in Crohn's Disease: A Nationwide Cohort Study.

OBJECTIVE: To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients. SUMMARY OF BACKGROUND DATA: CD treatment has changed considerably over the past decades. The effect of these advances on the necessity of intestinal resections and the risk of re-resection is unclear. METHODS: In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines. RESULTS: The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from 1.9/100,000 (1991) to 0.2/100,000 (2015). A significantly steeper-decrease was observed before 1999 (slope ­0.13) as compared to subsequent years (slope ­0.03) (p<0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36-0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18-0.34) in 2015 as compared to 1991. CONCLUSION: Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection.

Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.

BACKGROUND & AIMS: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. METHODS: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. RESULTS: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. CONCLUSION: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

The vanishing duodenal polyp: mesenteric invagination presenting as duodenal pseudopolyp.

Duodenal polypoid masses are an uncommon finding mainly diagnosed incidentally at endoscopy or surgery. We report a 39-year-old female patient with symptoms of intermittent stabbing pain in the upper right abdominal quadrant and an iron deficiency anaemia, without complaints of weight loss, haematemesis or melaena. A duodenal polyp and acute duodenitis have been described during endoscopic examinations and CT and ultrasound. Surgical excision of the polyp was advised. Intraoperatively, an elongated duodenum was remarkable; however, at duodenotomy, no polyp was found, nor during intraoperative endoscopy. Looking back at the endoscopy and imaging results, it was noted that the polyp varied in size and location. It was therefore concluded that we dealt with the pseudopolyp phenomenon, caused by invagination of the duodenal wall and its mesentery into the duodenum, presenting as a lipomatous pseudopolyp. Telescopic invagination of the duodenal wall was facilitated by the elongated hypermobile duodenum.

Similar Short- and Long-term Colectomy Rates with Ciclosporin and Infliximab Treatment in Hospitalised Ulcerative Colitis Patients.

BACKGROUND AND AIMS: Ciclosporin A [CsA] and infliximab [IFX] are similarly effective in preventing short-term colectomy in ulcerative colitis [UC] patients, but long-term data are scarce. We aimed to compare short- and long-term efficacy of CsA and IFX by analysing colectomy rates and failure of remission-induction treatment as outcome parameters for treatment success. METHODS: We retrospectively studied hospitalised UC patients who received CsA or IFX for moderate-to-severe UC, between January 2000 and April 2014. The primary endpoint was time to colectomy, and treatment failure [defined as colectomy or another remission-induction treatment with corticosteroids, CsA, or IFX] was used as secondary endpoint. Variables possibly affecting colectomy outcomes were analysed. RESULTS: A total of 55 patients were studied for colectomy outcome and 58 patients for treatment failure. A significantly longer follow-up duration was available for CsA-treated patients [p < 0.001, both subcohorts]. Patients showed comparable patient- and disease-specific characteristics. Colectomy rates did not differ significantly at 3, 12, and 36 months: 36% versus 29%, 58% versus 48%, and 64% versus 67% for CsA- and IFX-treated patients, respectively. Multivariate Cox regression analysis revealed the lowest hazard ratio [HR] for colectomy in patients concomitantly using thiopurines: HR 0.28 (confidence interval [CI] 0.13-0.64), p = 0.002. Treatment failure rates were not significantly different at 3, 12 and 36 months: 35% versus 48%, 51% versus 68%, and 62% versus 83% for CsA- and IFX-treated patients, respectively. CONCLUSIONS: Treatment with CsA and IFX is similarly effective in preventing short- and long-term colectomy in hospitalised UC patients. Furthermore, failure rates of these remission-induction treatments were comparable.

Serum Concentration of Anti-TNF Antibodies, Adverse Effects and Quality of Life in Patients with Inflammatory Bowel Disease in Remission on Maintenance Treatment.

BACKGROUND AND AIMS: High serum concentrations of infliximab [IFX] and adalimumab [ADA] may be associated with adverse effects in patients with inflammatory bowel disease [IBD]. We aimed to investigate whether high anti-tumour necrosis factor [TNF] trough levels [TLs] were associated with toxicity and impaired quality of life [QoL]. METHODS: We conducted a prospective cohort study in IBD patients in clinical and biochemical remission on IFX or ADA maintenance therapy. Trough serum concentrations and antidrug antibodies were measured in addition to biochemical markers of inflammation in serum and stool to confirm quiescent disease. QoL was assessed using the Inflammatory Bowel Disease Questionnaire and 36-item short form]. Side effects such as fatigue and arthralgia were measured with a visual analogue score [VAS]. Skin toxicity was reported with a European Organization for Research and Treatment of Cancer-derived score. RESULTS: In all, 252 IBD patients on maintenance anti-TNF therapy were screened, of whom 95 [73 with Crohn's disease, 22 with ulcerative colitis; 72 on IFX, 23 on ADA] were in clinical and biochemical remission and were included. Median TLs were 5.5 µg/ml and 6.6 µg/ml for IFX and ADA, respectively. Patients with anti-TNF TLs above median had lower IBDQ scores than patients with lower TLs [IBDQ 176 vs 187, p = 0.02], particularly regarding systemic symptoms and emotional status. A trend towards lower SF-36 and higher fatigue scores was observed in the higher anti-TNF TL group. Skin and arthralgia scores were not significantly different between the groups. CONCLUSIONS: IBD patients with higher anti-TNF serum concentrations had significantly lower disease-specific QoL. Fatigue, arthralgia, and skin lesions do not occur more often in these patients. These data are reassuring that high serum concentrations of anti-TNF antibodies are not toxic.

Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI).

OBJECTIVE: To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD). DESIGN: Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn's Disease Activity Index, Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed. CONCLUSIONS: Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00736983.

[Primary sclerosing cholangitis]. / Primaire scleroserende cholangitis.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown cause, with genetic predisposition in combination with environmental factors possibly playing a role. The diagnosis is made on the basis of a liver enzyme profile indicating cholestasis and characteristic bile duct abnormalities in cholangiography or the liver biopsy after excluding other causes. Approximately 80% of patients have concurrent inflammatory bowel disease (IBD), specifically ulcerative colitis in most patients. PSC predisposes to hepatobiliary malignancies such as cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma, as well as to colorectal carcinoma in patients with concurrent IBD.- UDCA and endoscopic bile duct dilatation relieve symptoms and improve the liver enzyme profile. Orthotopic liver transplantation is the only potentially curative therapy available.

Geographic pathology of Helicobacter pylori gastritis.

BACKGROUND AND AIM: Helicobacter pylori is etiologically associated with gastritis and gastric cancer. There are significant geographical differences between the clinical manifestation of H. pylori infections. The aim of this study was to compare gastric mucosal histology in relation to age among H. pylori-infected patients from different geographical areas using the same grading system. The prevalence of atrophy and intestinal metaplasia were also compared with the respective gastric cancer incidence in the different countries. METHODS: A total of 1906 patients infected with H. pylori from seven countries were evaluated. Entry criteria included H. pylori positive cases with antral and corpus biopsies between the ages of 18 and 75 years. The minimum number of cases required from a country was 100. Hematoxylin-eosin stained biopsies from antrum and corpus were scored semiquantitatively using the parameters suggested by the Sydney Classification System. Statistical evaluation was performed using Kruskal-Wallis test and Spearman's rank correlation test. RESULTS: The severity of gastric atrophy varied among the different groups with the highest scores being present in Japan. The lowest scores were found in four European countries and in Thailand. The scores for intestinal metaplasia were low in general except for Xi-an, Japan, and Shanghai. For all the countries, the presence of atrophy in the antrum correlated well (r = 0.891) with the incidence of gastric cancer. CONCLUSION: Using a standardized grading system in a large study of H. pylori-related geographic pathology, we found major differences in the overall prevalence and severity of H. pylori gastritis in relation to age. These differences mirrored the respective incidences of gastric cancer in those geographical areas.