A. Massari

Mucosal Healing Predicts Late Outcomes After the First Course of Corticosteroids for Newly Diagnosed Ulcerative Colitis

BACKGROUND & AIMS It is uncertain whether mucosal healing after the first course of corticosteroids therapy predicts outcome in patients with ulcerative colitis (UC). We evaluated whether early clinical and endoscopic responses to this therapy are associated with late outcomes in UC. METHODS Patients with newly diagnosed UC who were prescribed corticosteroid therapy (n = 157) were followed up for 5 years. They were evaluated using clinical (Powel-Tuck [PT]) and endoscopic (Baron) indexes after 3 and 6 months, then every 6 months. Outcomes at month 3 (early response) were used to identify patients with complete (group A: PT, 0-1; Baron, 0), partial (group B: PT, 0-1; Baron, 1-3), or no response (group C: persistence of clinical and endoscopic activity). The association between early and late outcomes was assessed. RESULTS After 5 years, there were significant differences between complete and partial responders in the rates of hospitalization (25% in group A vs 48.7% in group B; P = .0152; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.21-6.72), immunosuppression therapy (5% in group A vs 25.6% in group B; P = .0030; OR, 6.55; 95% CI, 1.67-25.67), colectomy (3.3% in group A vs 18.0% in group B; P = .0265; OR, 6.34; 95% CI, 1.24-32.37), and their combination (26.7% in group A vs 48.7% in group B; P = .0249; OR, 2.61; 95% CI, 1.12-6.11). After multivariate analysis, lack of mucosal healing was the only factor associated with negative outcomes at 5 years (immunosuppressors: hazard risk [HR], 10.581; 95% CI, 2.193-51.039; P = .0033; hospitalization: HR, 3.634; 95% CI, 1.556-8.485; P = .0029; colectomy: HR, 8.397; 95% CI, 1.278-55.186; P = .0268). CONCLUSIONS No mucosal healing after corticosteroid therapy is associated with a more aggressive disease course.

Prevalence and pathogenesis of anemia in inflammatory bowel disease. Influence of anti-tumor necrosis factor-α treatment

Background Anemia is a common complication of inflammatory bowel disease, but its epidemiology may be changing due to earlier diagnosis and improved treatments. We investigated the prevalence and pathogenesis of anemia in patients with inflammatory bowel disease. Design and Methods In a cross-sectional study 263 out-patients with inflammatory bowel disease (165 with Crohn’s disease, 98 with ulcerative colitis) were investigated. The influence of time from diagnosis, disease activity, inflammation and the status of iron and hematinic vitamins on the level of hemoglobin and prevalence of anemia were evaluated. In a second group of 27 patients with Crohn’s disease, undergoing anti-tumor necrosis factor-α treatment with infliximab because of refractory or fistulizing disease, we determined the effects of infliximab on disease activity, hemoglobin, serum erythropoietin levels, iron status and inflammation. Results In all, 104 of the 263 patients with inflammatory bowel disease were anemic. Age, gender and azathioprine treatment had no influence on anemia. The prevalence of anemia was highest at diagnosis (65%), decreased during the first 4 years after disease onset, and was stable thereafter. Active disease was associated with higher rates of anemia. At diagnosis most anemic patients had anemia of chronic disease; during follow-up iron deficiency and multifactorial forms of anemia became more prevalent. Eighteen of 27 patients undergoing treatment with infliximab were anemic; most of them had anemia of chronic disease. Infliximab reduced disease activity and improved anemia in 12 patients. This was mediated by an increased production of erythropoietin for the degree of anemia. In vitro infliximab increased the growth of erythroid progenitors from the peripheral blood of patients with active disease. Conclusions Anemia is a common problem in out-patients with inflammatory bowel disease; the prevalence and severity of anemia are related to the activity of the bowel disorder. The pathogenesis of anemia changes during the course of the disease, with anemia of chronic disease having a major role at diagnosis and iron deficiency and multifactorial forms of anemia during follow-up. In patients requiring anti-tumor necrosis factor-α treatment, response to therapy improves erythropoiesis.

Maintenance Treatment With Azathioprine in Ulcerative Colitis: Outcome and Predictive Factors After Drug Withdrawal

OBJECTIVES:Whether the duration of maintenance treatment with azathioprine (AZA) affects the outcome of ulcerative colitis (UC) is unclear. We investigated clinical outcomes and any predictive factors after withdrawal of AZA in UC.METHODS:In this multicenter observational retrospective study, 127 Italian UC patients, who were in steroid-free remission at the time of withdrawal of AZA, were followed-up for a median of 55 months or until relapse. The frequency of clinical relapse or colectomy after AZA withdrawal was analyzed according to demographic, clinical, and endoscopic variables.RESULTS:After drug withdrawal, a third of the patients relapsed within 12 months, half within 2 years and two-thirds within 5 years. After multivariable analysis, predictors of relapse after drug withdrawal were lack of sustained remission during AZA maintenance (hazard ratio, HR 2.350, confidence interval, CI 95% 1.434–3.852; P=0.001), extensive colitis (HR 1.793, CI 95% 1.064–3.023, P=0.028 vs. left-sided colitis; HR 2.024, CI 95% 1.103–3.717, P=0.023 vs. distal colitis), and treatment duration, with short treatments (3–6 months) more disadvantaged than >48-month treatments (HR 2.783, CI 95% 1.267–6.114, P=0.008). Concomitant aminosalicylates were the only predictors of sustained remission during AZA therapy (P=0.009). The overall colectomy rate was 10%. Predictors of colectomy were drug-related toxicity as the cause of AZA withdrawal (P=0.041), no post-AZA drug therapy (P=0.031), and treatment duration (P<0.0005).CONCLUSIONS:Discontinuation of AZA while UC is in remission is associated with a high relapse rate. Disease extent, lack of sustained remission during AZA, and discontinuation due to toxicity could stratify relapse risk. Concomitant aminosalicylates were advantageous. Prospective randomized controlled trials are needed to confirm whether treatment duration is inversely associated with outcome.

Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study.

Crohns disease (CD) is associated with a higher type-1-helper T cell (Th1) cytokine expression, whereas ulcerative colitis (UC) appears to express a modified Th2 response. In addition to its classic role in calcium homeostasis, calcitriol, the hormonal active form of vitamin D, exerts immunoregulatory effects such as modulation of Th1/Th2 cytokines. Therefore, calcitriol administration could modify immune dysfunction in CD and UC. Nine patients with UC [M/F: 5/4; mean age 47 years, remission(R)/active(A) disease: 7/2], 8 patients with CD [M/F: 2/6; mean age 36, R/A 5/3] and 6 healthy controls (HC) [M/F: 3/3, mean age 46] were enrolled. Peripheral blood was collected after a drug-washout of 15 days and peripheral blood mononuclear cells were stimulated with mitogens alone or in the presence of physiological concentrations of calcitriol (100 pg/ml). Type 1 (IL-2, TNF-α, IFN-γ) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-α production was significantly higher both in UC (p=0.0002) and CD (p=0.0001) patients, at baseline and after incubation with calcitriol (UC p=0.0003, CD p=0.0009). The effects of calcitriol incubation were: 1) reduced IFN-γ (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-α production in CD (p=0.032); 3) no significant effects in HC. Calcitriol increased, albeit not significantly, IL-10 production in UC compared to CD patients (p=0.09). These results suggest an important modulatory role of vitamin D in the Th1/Th2 immune response. The observation that the effect of this modulation was different in CD compared to UC patients provides an interesting area of research into the pathogenesis and treatment of these inflammatory conditions.

The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar.

Background: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohns disease. Methods: A prospective, multicenter, cohort study using a structured database. Results: Consecutive patients (313 Crohns disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti–tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti–tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05–7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). Conclusions: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Prevalence and clinical significance of sonographic evidence of mesenteric fat alterations in Crohn's disease

Background: Mesenteric adipose tissue hypertrophy is a frequent sonographic finding in Crohns disease (CD). This study assessed its sonographic prevalence, the correlation with the degree of clinical or biochemical activity of the disease, and its impact on disease outcome in CD patients. Methods: In all, 185 consecutive CD patients underwent bowel ultrasound to assess the presence of mesenteric fat tissue alteration as well as thickness and echopattern of the bowel wall, site and extent of CD, and presence of stenosis, fistulas, and abscesses. Clinical and biochemical parameters of disease activity were also assessed. Multiple logistic regression analysis was used to identify variables related to mesenteric adipose tissue alteration. Results: Mesenteric adipose tissue alteration, detected in 88 (47.6%) patients, showed a significant correlation both with clinical and biochemical CD activity and with internal fistulas, bowel wall thickness, and length of thickened bowel wall. Logistic regression analysis showed that internal fistulas (odds ratio [OR] = 13.5), thickened bowel wall (OR = 7.6), C‐reactive protein (OR = 6.1), CD Activity Index (CDAI) (OR = 3.1), and length of diseased bowel walls (OR = 2.6) were significantly associated with mesenteric adipose tissue alteration. Of the 111 patients with quiescent CD, 22 showed mesenteric adipose tissue hypertrophy. These patients did not show increased risk of relapse compared with quiescent patients without mesenteric fat alteration. Conclusions: Mesenteric adipose tissue alteration is correlated with biochemical and clinical activity of CD and with internal fistulas and increased bowel wall thickness. In quiescent CD, mesenteric hypertrophy does not appear to be a risk factor of relapse.

Peripheral regulatory T cells and serum transforming growth factor‐β: Relationship with clinical response to infliximab in Crohn's disease

Background: CD4+Foxp3+ regulatory T cells (Treg) inhibit T‐cell proliferation in vitro and are effective in suppressing colitis in mouse models. Tumor necrosis factor (TNF)‐&agr;, which is centrally involved in Crohns disease (CD) pathogenesis, also impairs Treg function. Here we investigated the influence of anti‐TNF therapy on Treg frequency and function in CD. Methods: Twenty CD patients were treated with infliximab administered at weeks 0, 2, and 6. Blood was collected immediately before the first infusion and after 10 weeks. Treg frequency was quantified by flow cytometry. Treg function was measured using a standard coculture assay. Serum levels of transforming growth factor (TGF)‐&bgr;1 and interleukin (IL)‐10 were measured by enzyme‐linked immunosorbent assay (ELISA). Results: Pretreatment Treg frequency and serum TGF‐&bgr;1 levels were significantly higher in nonresponder than responder patients. Clinical improvement in 12 CD patients was associated with a significant increase of Treg frequency after 10 weeks. Treg were functionally active before and after treatment with infliximab, both in responder and nonresponder CD patients. In responder patients the restoration of Treg pool was accompanied by a parallel significant increase of serum TGF‐&bgr;1 and IL‐10. No significant change in the elevated Treg or serum TGF‐&bgr;1 was seen in nonresponder patients. Conclusions: This study suggests that there may be a relationship between numbers of Treg in the blood, serum TGF‐&bgr;1, and response to infliximab; however, further prospective studies are needed. (Inflamm Bowel Dis 2010)

Serum hepcidin in inflammatory bowel diseases: biological and clinical significance.

Background: Hepcidin, a peptide produced by hepatocytes, regulates body iron homeostasis. Inflammation increases serum hepcidin, and its determination can be useful in the differential diagnosis of anemias during inflammatory diseases. Methods: We measured serum hepcidin-25 and hepcidin-20 isoforms in 54 patients with inflammatory bowel diseases (IBD) and 54 reference subjects (36 healthy controls and 18 anemic patients without inflammation or renal failure). Disease activity, blood counts, iron status, and erythropoiesis-related parameters were obtained for all study subjects. Results: In IBD hepcidin-25, the peptide bioactive isoform correlated positively with C-reactive protein and serum ferritin; an inverse correlation was observed with transferrin, the soluble transferrin receptor, and the soluble transferrin receptor to Log(ferritin) ratio. Similar correlations were found in reference subjects. Patients with anemia of inflammation had higher hepcidin-25 levels than those with iron deficiency anemia or a combination of iron deficiency anemia and inflammation (P = 0.0061). In patients with inflammation and serum ferritin concentration 100 to 200 ng/mL, hepcidin-25 was low, suggesting that these patients had iron deficiency. A serum hepcidin-25 concentration below 2.0 nM differentiated 85% of patients with iron deficiency anemia (with or without inflammation) from patients with anemia of inflammation. In IBD, hepcidin-20 correlated with both hepcidin-25 and C-reactive protein. Conclusions: In IBD, iron stores, inflammation, and iron requirement for erythropoiesis influence serum hepcidin-25. Hepcidin-25 determination can be useful in the differential diagnosis of IBD-associated anemias. Serum hepcidin-20 is linked to hepcidin-25, but inflammation has an independent regulatory role on its concentration, indicating that hepcidin-20 may have a biological function.

Appropriateness and diagnostic yield of colonoscopy in the management of patients with ulcerative colitis: a prospective study in an open access endoscopy service.

Background: Colonoscopy is frequently performed in ulcerative colitis (UC), but its benefit in the management of the disease is a matter of debate. The objective was to determine the clinical impact of colonoscopy in UC. Methods: Consecutive patients with UC undergoing colonoscopy were studied. The design and main outcome measurement was appropriateness of indications, evaluated according to guidelines. Endoscopic findings altering the management of the patients were registered. The endoscopists management decisions based on patients clinical picture were compared with those selected after endoscopy. Need for further investigations was recorded. Endpoints for colonoscopy‐improving management were prospectively defined: change in medical therapy, need for adjuctive procedures, identification or exclusion of cancer, adenomatous polyps, or other conditions with clinical impact. The setting was an open access endoscopy service in a tertiary care center. Results: In all, 507 patients (268 male, 239 female, mean age 42 years) were included. Colonoscopy was indicated in 60.8% of cases. In 46% of patients endoscopy revealed a significant lesion; this rate was higher for indicated (67.2) than for not indicated procedures (13.5%, P < 0.0001). The endoscopists decision was altered by the endoscopic finding in 7.6% of cases and was not different between appropriate and inappropriate procedures. Conclusions: Endoscopy is a potent tool in the management of UC if correctly used. However, in the majority of cases a correct therapeutic decision may be established simply on the basis of the clinical picture. Relevant endoscopic findings have a relatively low impact on the medical treatment, but may have a very important value in the prognostic assessment of the disease.

The Time Course of Diagnostic Delay in Inflammatory Bowel Disease Over the Last Sixty Years: An Italian Multicentre Study

Background and Aims Inflammatory bowel disease [IBD] patients are still under-diagnosed or diagnosed with serious delay. We examined whether diagnostic delay [DD] in IBD has changed over the last 60 years, and explored the risk factors of longer DD. Methods In total, 3392 IBD patients recorded in the registry of four IBD Italian centres were divided according to the year of diagnosis into a historical cohort [HC: 1955-84] and modern cohort [MC: 1985-2014]. DD, i.e. time lapse between onset of symptoms indicative of IBD and definitive diagnosis, was divided into four sub-periods [0-6, 7-12, 13-24, >24 months], which were correlated with age and disease location/behaviour at diagnosis. Results Median DD in IBD was 3.0 months, it was significantly [P < 0.0001] higher in Crohns disease [CD] [7.1 months] than in ulcerative colitis [UC] [2.0 months], and did not differ either between the HC and the MC or over the last three decades. However, the proportion of patients with a DD>24 months was significantly [P < 0.0001] higher in the HC [26.0%] than in the MC [18.2%], and the same trend was evident over the last three decades [1985-94: 19.9%; 1995-2004: 16.4%; 2005-14: 13.9%; P = 0.04]. At logistic regression analysis, age at diagnosis >40 years (CD: odds ratio 1.73, 95% confidence interval [CI] 1.31-2.28, P < 0.0001; UC: 1.41, 95% CI 1.02-1.96, P = 0.04) and complicated disease at CD diagnosis [1.39, 95% CI 1.06-1.82, P = 0.02] were independently associated with a DD>24 months. Conclusions DD duration has not changed over the last 60 years in Italy, but the number of IBD patients with a longer DD significantly decreased. Older age at diagnosis and a complicated disease at CD diagnosis are risk factors for longer DD.