Factors correlated with transmural healing in patients with Crohn's disease in long-term clinical remission on anti-TNF medication.

BACKGROUND & AIMS: Transmural healing is a long-term target for patients with Crohn's disease. Factors contributing to its promotion are poorly understood. This study assessed factors correlating with transmural healing based on intestinal ultrasound, in patients in long-term clinical remission on anti-TNF. METHODS: 68 consecutive Crohn's patients on adalimumab (50) or infliximab (18) therapy with clinical remission ≥1 year were recruited and assessed for clinical features, trough serum levels of anti-TNF and intestinal ultrasound findings. Univariate analysis and multivariate binary logistic regression analysis identified variables independently associated with bowel wall thickening behavior. RESULTS: Sixty eight patients were in remission for a mean of 4.1 years. Thirty-six patients (52.9 %) showed anti-TNF trough levels below the normal threshold. Twenty-two patients (38.4 %) showed transmural healing, 32 (47.1 %) transmural response, and 26 (38.2 %) no treatment response. Transmural healing correlated with higher BMI and lower baseline bowel wall thickening; transmural response correlated with short Crohn's disease duration, high drug levels, and with non-stricturing phenotype. Treatment non-response correlated with lower BMI, lower drug levels, higher baseline bowel wall thickening, and stricturing phenotype. CONCLUSIONS: Lack of transmural healing in stable remission Crohn's patients on anti-TNF therapy is multifactorial, mainly due to low anti-TNFs trough levels, development of strictures, and higher baseline bowel wall thickening at treatment initiation.

Continuous clinical remission with biologics in ulcerative colitis: the 'AURORA' comparison study.

OBJECTIVES: Comparative trials among biological drugs for the treatment of ulcerative colitis (UC) provided conflicting results. After patent expire of infliximab originator, adalimumab, infliximab biosimilar, golimumab and vedolizumab have been approved in Italy.We compared the efficacy of these four biologics in UC according to the concept of continuous clinical remission (CCR). METHODS: In a retrospective, multicentre study, all UC patients treated with adalimumab, infliximab biosimilar, golimumab or vedolizumab between 2014 and 2019 were included. All drugs were compared to each other according to the 1-year CCR rate, defined as Mayo partial score ≤2, with bleeding subscore = 0, without any relapse or optimization with dose escalation, topical treatments or steroid use after first clinical remission. RESULTS: Four-hundred sixteen patients (adalimumab = 90, infliximab biosimilar = 105, golimumab = 79, vedolizumab = 142) were included. CCR was achieved in similar percentages among the groups (33%, 37%, 28%, 37%, respectively). All drugs were equivalent in biologic-naive patients, while vedolizumab was better than a second anti-TNFα in prior anti-TNFα agent failures. No differences were found according to type of adverse events or severe adverse events. CONCLUSIONS: Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year. Changing to vedolizumab is more effective than switching to another anti-TNFα in TNFα failures.

Circulating Fibroblast Activation Protein as Potential Biomarker in Patients With Inflammatory Bowel Disease.

A major concern in the management of Inflammatory Bowel Disease (IBD) is the absence of accurate and specific biomarkers to drive diagnosis and monitor disease status timely and non-invasively. Fibroblast activation protein (FAP) represents a hallmark of IBD bowel strictures, being overexpressed in stenotic intestinal myofibroblasts. The present study aimed at evaluating the potential of circulating FAP (cFAP) as an accessible blood biomarker of IBD. Quantitative determination of cFAP was performed by enzyme-linked immunosorbent assay on plasma samples prospectively collected from patients with IBD and control subjects. A discrimination model was established on a training set of 50% patients and validated on independent samples. Results showed that cFAP concentration was reduced in patients with IBD when compared to controls (p < 0.0001). Age, sex, smoking, disease location and behavior, disease duration and therapy were not associated with cFAP. The sensitivity and specificity of cFAP in discriminating IBD from controls were 70 and 84%, respectively, based on the optimal cutoff (57.6 ng mL-1, AUC = 0.78). Predictions on the test set had 57% sensitivity, 65% specificity, and 61% accuracy. There was no strong correlation between cFAP and routine inflammatory markers in the patients' population. A subgroup analysis was performed on patients with Crohn's disease undergoing surgery and revealed that cFAP correlates with endoscopic mucosal healing. In conclusion, cFAP deserves attention as a promising blood biomarker to triage patients with suspected IBD. Moreover, it might function as a biomarker of post-operative remission in patients with Crohn's disease.

Anti-tumour necrosis factor α antibodies and circulating lymphocyte phenotypes in inflammatory bowel disease.

OBJECTIVE: Circulating lymphocyte subtypes are not fully explored parameters for monitoring chronic T cell activation during inflammatory bowel disease (IBD). Tumor necrosis factor α (TNFα), one of the main mediators of IBD related inflammation induces expression of CD70 on T cells. CD70 limits T cell expansion and controls CD27 receptor on activated B lymphocytes. Aim of this study was to assess the number and the frequency of CD70+ T cells and CD27+ B cells in IBD patients during inactive phase of the disease under or without anti-TNFα treatment. DESIGN: We studied 91 patients with inactive IBD, 31 untreated, 29 treated with infliximab (IFX), and 31 treated with adalimumab (ADA). Lymphocyte phenotypes were assessed by flow cytometry using anti-CD45, CD19, CD27, CD3, and CD70 monoclonal antibodies. IFX and ADA actual capacity of TNFα neutralization in serum was estimated by the recoveryELISA technique. RESULTS: Whereas CD3+ T cells were increased in treated compared to untreated patients, the percentage of the CD70+ T cells was significantly lower in treated patients indicating a 'cooling' effect of the biological therapy. This effect differs between samples according to the therapeutic range of the circulating drug. Although the CD19+ B-cell percentage tended to be lower in treated patients, CD19+27+ memory B cells did not show significant differences between groups. CONCLUSIONS: Frequency of peripheral blood CD70+ T cells was significantly reduced by treatment with anti-TNFα antibodies. Monitoring of this parameter of T cells can give better insight to the disease progression and therapy application in IBD patients.

Risk of COVID 19 in patients with inflammatory bowel diseases compared to a control population.

BACKGROUND: It is unclear whether patients with inflammatory bowel disease (IBD) are at increased risk of COVID-19. OBJECTIVES: This observational study compared the prevalence of COVID-19 symptoms, diagnosis and hospitalization in IBD patients with a control population with non-inflammatory bowel disorders. METHODS: This multicentre study, included 2733 outpatients (1397 IBD patients and 1336 controls), from eight major gastrointestinal centres in Lombardy, Italy. Patients were invited to complete a web-based questionnaire regarding demographic, historical and clinical features over the previous 6 weeks. The prevalence of COVID-19 symptoms, diagnosis and hospitalization for COVID-19 was assessed. RESULTS: 1810 patients (64%) responded to the questionnaire (941 IBD patients and 869 controls). IBD patients were significantly younger and of male sex than controls. NSAID use and smoking were more frequent in controls. IBD patients were more likely treated with vitamin-D and vaccinated for influenza. Highly probable COVID-19 on the basis of symptoms and signs was less frequent in the IBD group (3.8% vs 6.3%; OR:0.45, 95%CI:0.28-0.75). IBD patients had a lower rate of nasopharyngeal swab-PCR confirmed diagnosis (0.2% vs 1.2%; OR:0.14, 95%CI:0.03-0.67). There was no difference in hospitalization between the groups (0.1% vs 0.6%; OR:0.14, 95%CI:0.02-1.17). CONCLUSION: IBD patients do not have an increased risk of COVID-19 specific symptoms or more severe disease compared with a control group of gastroenterology patients.

Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study.

OBJECTIVES: COVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear. DESIGN: This Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death). RESULTS: Between 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death. CONCLUSIONS: Active IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.

Use, effectiveness and tolerability of budesonide-MMX in ulcerative colitis: A real-life experience.

Background: Budesonide-MMX has an established role in the management of relapsing mild-to-moderate ulcerative colitis. Data regarding effectiveness and tolerability in real-life clinical practice are limited. Aim: The aim of this study was to assess the use of budesonide-MMX in ulcerative colitis, as well as short-term effectiveness and tolerability in real-life practice. Methods: We conducted a retrospective study of adult patients with mild-to-moderate ulcerative colitis treated with budesonide-MMX at four tertiary inflammatory bowel disease centres in Italy from June 2016 to February 2018. Demographic and clinical features of patients, the use of budesonide-MMX, disease course and concomitant therapy were recorded. The primary outcome assessed was clinical remission at 2 months. Results: A total of 82 patients with active mild-to-moderate ulcerative colitis were included in the study with a mean age of 45.9 years and a median partial Mayo Score of 4 (interquartile range 3-5). A total of 41 patients were male. Overall, 36 had extensive colitis, 38 left-sided colitis and eight proctitis. Treatments at the time of inclusion included 10 patients receiving biologic therapy, seven azathioprine and 54 mesalazine or salazopyrin. The main reasons for the addition of budesonide-MMX were clinical relapse (47.5%) or inadequate response to current therapy (39.0%). In total, 50% of patients achieved clinical remission, whereas 9.8% had clinical improvement. No response was noted in 40.2% of subjects. Using multivariate binary logistic regression, a moderate degree of activity was the main independent predictor of non-response. Eight significant adverse effects were reported in six patients with three discontinuing treatment. Conclusion: In real-life clinical practice, budesonide-MMX is commonly used in combination with other therapies, both for acute disease flares and for partial response to therapy.

The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy.

BACKGROUND: We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS: A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS: Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naïve to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS: In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

Totally laparoscopic, multi-stage, restorative proctocolectomy for inflammatory bowel diseases. A prospective study on safety, efficacy and long-term results.

BACKGROUND: Laparoscopic ileo-pouch-anal anastomosis (IPAA) has been reported as having low morbidity and several advantages. AIMS: To evaluate safety, efficacy and long-term results of laparoscopic IPAA, performed in elective or emergency settings, in consecutive unselected IBD patients. METHODS: All the patients received totally laparoscopic 2-stage (proctocolectomy and IPAA - stoma closure) or 3-stage (colectomy - proctectomy and IPAA - stoma closure) procedure according to their presentation. RESULTS: From July 2007 to July 2016, 160 patients entered the study. 50.6% underwent a 3-stage procedure and 49.4% a 2-stage procedure. Mortality and morbidity were 0.6% and 24.6%. Conversion rate was 3.75%. 8.7% septic complications were associated with steroids and Infliximab treatment (p = 0.0001). 3-stage patients were younger (p = 0.0001), with shorter disease duration (p = 0.0001), minor ASA scores of 2 and 3 (p = 0.0007), lower inflammatory index and better nutritional status (p = 0.003 and 0.0001), fewer Clavien-Dindo's grade II complications (p = .0001), reduced rates of readmission and reoperation at 90 days (p = 0.03), and shorter hospitalization (p = .0001), but with similar pouch and IPAA leakage, compared to 2-stage patients. 8 years pouch failure and definitive ileostomy were 5.1% and 3.7%. CONCLUSION: A totally laparoscopic approach is safe and feasible, with very low mortality and morbidity rates and very low conversion rate, even in multi-stage procedures and high-risk patients.

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 Crohn's 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.

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 Crohn's disease. METHODS: A prospective, multicenter, cohort study using a structured database. RESULTS: Consecutive patients (313 Crohn's 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.

Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment.

Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11-dehydro-thromboxane (TX) B2 (11-dehydro-TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)-α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6-week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8-iso-PGF2α and 11-dehydro-TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX-dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF-α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.

Overview of biological therapy in ulcerative colitis: current and future directions.

The treatment of ulcerative colitis (UC) has changed over the last decade. It is extremely important to optimize the therapies which are available nowadays and commonly used in daily clinical practice, as well as to stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. Therefore, it is mandatory to identify the patients' prognostic variables associated with an aggressive clinical course and to test the most potent therapies accordingly. To date, the conventional therapeutic approach based on corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid) or immunosuppressive agents is commonly used as a first step to induce and to maintain remission. However, in recent years, knowledge of new pathogenetic mechanisms of ulcerative colitis have allowed us to find new therapeutic targets leading to the development of new treatments that directly target proinflammatory mediators, such as TNF-alpha, cytokines, membrane migration agents, cellular therapies. The aim of this review is to provide the most significant data regarding the therapeutic role of drugs in UC and to give an overview of biological and experimental drugs that will become available in the near future. In particular, we will analyse the role of these drugs in the treatment of acute flare and maintenance of UC, as well as its importance in mucosal healing and in treating patients at a high risk of relapse.

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.

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.

Peripheral regulatory T cells and serum transforming growth factor-ß: 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)-α, which is centrally involved in Crohn's 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)-ß1 and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Pretreatment Treg frequency and serum TGF-ß1 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-ß1 and IL-10. No significant change in the elevated Treg or serum TGF-ß1 was seen in nonresponder patients. CONCLUSIONS: This study suggests that there may be a relationship between numbers of Treg in the blood, serum TGF-ß1, and response to infliximab; however, further prospective studies are needed.

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

Isolated ampullary adenoma causing biliary obstruction.

This is an interesting case of an isolated ampullary adenoma causing biliary obstruction that required surgical excision. We describe a patient who presented with a six month history of recurrent attacks of typical biliary pain radiating from the right upper quadrant of the abdomen to the back, nausea and vomiting, which we attributed to a large pedunculated tubulovillous adenoma. Abdominal ultrasound and endoscopic ultrasonography provided useful information in the diagnostic assessment of ampullary adenoma. Sporadic duodenal adenomas are an increasingly recognized condition in those with familial adenomatous polyposis syndromes as well as sporadic cases.