Steroid-dependent Ulcerative Colitis Patients Research Articles

P066 Exploration of critical molecules for optimizing treatment by analyzing in flammatory cytokines in the intestinal mucosa of patients with Inflammatory Bowel Disease

Abstract Background Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). Research into the cytokine biology of IBD has nurtured the dogmatic view that distinct immunotypes characterize different IBD subtypes. Recently, many biologics have emerged as the treatment options for IBD patients. Still, it is challenging to establish biomarkers for predicting their effectiveness because the cytokines that determine the IBD clinical phenotype vary in individual patients. Therefore, this study aims to explore critical molecules for optimizing treatment by analyzing inflammatory cytokines in the intestinal mucosa of IBD patients. Methods From September 2019, to February 2020, patients with ulcerative colitis (UC) and Crohn’s disease (CD) who underwent colonoscopy or flexible sigmoidoscopy, and the control group, patients who received colorectal polypectomy at our institution, were enrolled in the study. We took biopsies from inflamed ileal or colonic mucosa. We analyzed the gene expression of various inflammatory cytokines by real-time PCR using RT2 Profiler PCR Array (96-Well Format) Human Inflammatory Cytokines & Receptors (QIAGEN). Cytokines not included in this array were subjected to real-time PCR separately. Based on these data, we investigated the relationship between mucosal cytokines and clinical characteristics. Results The total number of patients was 23 (control 5, UC 12, CD 6) cases, the median age was 51 years (18–78), genders were fifteen males and eight females. Disease phenotype was divided into extensive colitis/ left-sided colitis/proctitis (10/1/1) in UC patients, and A1/A2/A3 (2/3/1), L1/L3 (2/4), B1/B1+p/B2/B3 (3/1/1/1) in CD patients. Seven patients were steroid-dependent, and six patients were refractory to the anti-TNFα agent. The higher gene expressions of CCR2/CXCL1/CXCL3/CXCL13, IL-8, IL-33, and SPP1 in inflamed mucosa of UC compared to those of CD (p<0.05). The positive correlation between Mayo score and IL-1R1 expression in intestinal mucosa was observed (r=0.68, p=0.028). The expression of IL-1β, IL-6, IL-8, and oncostatin M (OSM) was higher in steroid-dependent UC patients, and the primary non-responders to anti-TNFα therapies had higher expressions of IL-7 in colonic mucosa than the secondary non-responders in UC. Conclusion Our results suggest that UC exhibits different cytokine patterns in the intestinal mucosa from CD as reported previously. Exploration of cytokine expressions in the intestinal mucosa may lead to predicting refractory IBD. The identification of molecules that can predict therapeutic effectiveness helps to optimize IBD treatment in the future.

P588 Steroid sparing effect of adalimumab in cortisone–depended ulcerative colitis patients

Abstract Background Corticosteroids are indicated for induction of remission in moderate to severe ulcerative colitis (UC) patients. However, due to their adverse effects associated with long-term use, steroids are not indicated as a maintenance therapy. The aim of this study was to assess the steroid sparing effect of adalimumab (ADA) in steroid-dependent UC patients. Methods This is a prospective study carried out at a tertiary hospital center in Albania from 2016–2020, including consecutive moderate-to-severe UC patients. All patients received biologic therapy with subcutaneous ADA 160/80mg at weeks 0/2 followed by 40mg every 2 weeks. We evaluated the steroid-sparing effect of ADA measuring the number of steroid–free patients and the average steroid dose at baseline before initiating biologic treatment and at week 8, 24, 52, 104, 156. Clinical remission was defined as total Mayo score ≤ 2 points. Results We enrolled 26 UC patients, mean age 47.3 ± 16.1 (24–85) years, 55.6% were females. The average disease duration before starting ADA was 7.3 ± 7.0 years (range 1–33); 44.4% had pancolitis and 55.6% left side colitis. 8(29.6%) patients were on combination therapy with azathioprine. 17/26 (65.4%) patients were taking prednisone at the time of the first ADA injection with an average dose of 17.7mg. The number of steroid-free patients at week 8, 24, 52, 104 and 156 was 12/26 (46.2%), 16/26 (61.5%), 15/21 (71.4%), 11/14 (78.6%), 8/9 (88.9%) respectively. At the end of the follow-up (week 156), the proportion of steroid free patient was significantly higher than at baseline [88.9% (8/9) vs 34.6% (7/26), p=0.005]. The reduction of the average dose of prednisone (8.8 mg, 4 mg, 6.8mg, 3.8mg and 3,8mg at week 8, 24, 52, 104 and 156 respectively), was also statistically significant (p<0.01). Clinical remission rates were 7.7% (2/26) at week 8, 47.6% (10/21) at week 52, 42.9% (6/14) at week 104 and 44.4 % (4/9) at week 156. Conclusion In our cohort, ADA administration to moderate–to severe UC significantly reduced the steroid dose and the proportion of patients taking cortisone during 3 years follow-up.

Thiopurine Treatment in Ulcerative Colitis: A Critical Review of the Evidence for Current Clinical Practice.

Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC. Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE. Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo. All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC.

Low-dose azathioprine is effective in maintaining remission in steroid-dependent ulcerative colitis: results from a territory-wide Chinese population-based IBD registry.

Whether low-dose azathioprine (AZA) is effective in maintaining remission in patients with steroid-dependent ulcerative colitis (UC) remains unclear. We assessed the efficacy and safety of low-dose AZA in a Chinese population with UC. We identified steroid-dependent UC patients in clinical remission on AZA maintenance therapy from a territory-wide IBD Registry. Standard- and low-dose AZA were defined as at least 2 mg/kg/day and less than 2 mg/kg/day, respectively. Relapse rates were analyzed by Kaplan-Meier analysis and compared using log-rank test. Among 1226 UC patients, 128 (53% male, median duration on AZA 44 months) were included. Median maintenance AZA dose was 1.3 mg/kg/day. 97.7% of the patients were on concomitant oral 5-aminosalicylic acid. Cumulative relapse-free rates in patients on standard-dose and low-dose AZA were 71.2%, 52.8% and 45.2%, and 71.8%, 55.3% and 46.2% at 12, 24 and 36 months, respectively (p = 0.871). Relapse rate within 12 months was higher in patients who withdrew compared with those who maintained on AZA (52.6% versus 29.4%; p = 0.045). Mean corpuscular volume increased after AZA therapy in both of the low-dose [median (interquartile range, IQR): 88.2 (81.4-92.2) versus 95.1 (90.1-100.9) fl, p < 0.001] and standard-dose subgroups [median (IQR) 86.8 (76.9-89.9) versus 94.7 (85.9-99.7) fl, p < 0.001]. Leukopenia occurred in 21.1% of the patients. Patients on standard dose had a higher risk for leukopenia than those on low-dose AZA [odds ratio (OR) 3.9, 95% CI 1.9-8.2, p < 0.001]. In the Chinese population, low-dose AZA is effective for maintaining remission in steroid-dependent UC patients. Standard-dose AZA was associated with more than threefold increased risk of leukopenia.

Eficacia de adalimumab en el tratamiento de la colitis ulcerosa dependiente de corticoides

IntroductionSteroid dependency develops frequently (more than 30%) with regards to ulcerative colitis (UC) patients. Our aim was to evaluate the clinical efficacy of ADA in steroid-dependent UC patients. MethodsOpen-label, retrospective, consecutive, and multicentre study. Inclusion criteria were patients over 18 years old with UC and ECCO criteria of steroid-dependency. All patients received ADA treatment for induction (160/80mg) at weeks 0 and 2 and 40mg every 2 weeks thereafter. The main endpoint was clinical remission without steroids. Clinical response, mucosal healing and levels of C-reactive protein and calprotectine were also evaluated. Results are shown in percentages; associations were analyzed by multiple regression whenever appropriate. ResultsThirty-seven steroid-dependent UC patients treated with ADA: 65% E3. Twelve patients (32%) naive to anti-TNF and 25 (68%) had previously received infliximab. Forty-three percent needed ADA intensification. After induction 35% of patients were in remission and after 12 months 40% of patients were in remission without steroids. The mean partial Mayo score was 6.89 basal, 3.13 at month 6 and 2.33 at month 12 (P<.01). Mucosal healing was achieved in 48% of patients. Only 3 patients (8%) needed a colectomy. We did not observe any association between clinical characteristics and response to ADA, but after multivariate analysis patients with loss of response to ADA had a lower remission rates (HR=12.8; CI 95% 2.24-73.54; P=0.004). ConclusionsAdalimumab can be effective for clinical remission without steroids and mucosal healing in steroid-dependent UC. Loss of response to ADA is a predictive factor of poorer efficacy.

P-096 YI Comparative Response of Combination Therapy vs. Mono Therapy in Steroid Dependent Ulcerative Colitis Patients

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) characterized by a chronic relapsing/intermittent clinical course. Steroids offer efficient and prompt relief of symptoms in a high proportion of ulcerative colitis (UC). Although most patients initially respond to corticosteroids, after 1 year, approximately 25% become steroid-dependent. The aim of this prospective study was to assess whether the administration the efficacy of azathioprine (AZA) and mesalamine combination to AZA monotherapy in maintaining remission of steroid-dependent ulcerative colitis (UC). The present study was carried out in the Department of Gastroenterology, IMS, BHU, Varanasi, India. A total of 136 patients age sex matched were included in the study after written informed consent fulfilling inclusion and exclusion criteria's. Patients with steroid-dependent UC in remission were randomized to receive AZA alone (1.5 mg/kg) (group 1) or in combination with mesalamine (800 mg tid) (group 2). Each group had 59 patients. Patients were considered in remission when steroid was withdrawn, an Ulcerative Colitis Clinical Activity Index (UCCAI) score of <2, an Ulcerative Colitis Disease Activity Index (UCDAI) score of 0, and a negative colonoscopy and histology. Followup was carried out every monthly for 2 year. Clinical examination, hematological and biochemical test were carried out routinely. Sigmoidoscopy and completion of inflammatory bowel disease quality-of-life questionnaire (IBD-Q) and UCDAI every 3 months; and 3) total colonoscopy with biopsies at the end of the study. Out of 136 patients 110 patients were analysed and rest 18 (13.23%) were lost in followup and 4 patients in each group developed side effects or poor compliance with treatment and were withdrawn from the study. Five patients receiving monotherapy (group 1) relapsed after the first year of the study and 3 after the second year of the study (14.54%). In the combination group (group 2) 2 patients relapsed after the first year of study and 2 after the second year of the study (7.27%) having statistically significant when compared with group 1 (p<0.05). Relapse rates were significant whether analyzed by intention-to-treat or per protocol. There were no significant differences between groups in time to relapse or discontinuation of treatment, UCCAI, UCDAI, or IBD-Q scores. Adverse events were similar both the groups and statistically non significant. Patients with steroid-dependent UC successfully maintained in remission on AZA and mesalamine and however relapse rate were more common in patients on azathioprine alone.

Effectiveness of Antibiotic Combination Therapy Targeting Intestinal Bacteria for Ulcerative Colitis

Introduction: We previously demonstrated that antibiotic combination therapy is effective for induction and maintenance of ulcerative colitis (UC) remission (Am J Gastroenterol 2010;105:1820 We assessed whether the antibiotic combination therapy is effective for improving UC patients with disease type of disease severity, disease extension, and steroid-refractory or steroid-dependent. Methods: We enrolled 151 patients (mean age 37 years, male/female:94/57)in an open-label trial. These patients received three-times-daily by mouth amoxicillin 500 mg, tetracycline 500 mg and metronidazole 250 mg, for two weeks more, combined with conventional treatment. Symptom assessment and colonoscopic evaluation were performed before enrolment and at 3 months after treatment completion. Clinical response was defined as Mayo score decrease in ≥3 points and clinical remission as a score ≤4. Results: In extension of UC, response rates were 76.0% in proctitis, 77.0% in left-sided colitis and 77.0% in extensive colitis after the treatments. At 3months after the treatment, response rates were 76.0% in proctitis, 59.6% in left-sided colitis and 64.9% in extensive colitis. Moreover, after the treatments, remission rates were 36.0% in proctitis, 21.2% in left-sided colitis and 33.8% in extensive colitis. In addition, at 3months after the treatments, remission rates were 44.0% in proctitis, 25.0% in left-sided colitis and 28.4% in extensive colitis. On the other hand, response rates were 71.5% in mild, 76.4% in moderate and 88.9% in severe UC after the treatments. At 3months after the treatments, 53.6% in mild, 64.7% in moderate and 77.8% in severe UC. Remission rates were 42.9% in mild, 27.7% in moderate and 22.2% in severe after the treatments, and 28.6% in mild, 27.6% in moderate and 38.9% in severe at 3 months after the treatments. In steroid-refractory, dependent and non-steroid patients, response rates after the treatments were 80.7%, 73.8% and 81.6%, respectively. Moreover, response rates at 3 months after the treatments were 61.6% in steroid-refractory, 66.2% in steroid-dependent 65.0% in non-steroid patients. Conclusion: This study suggests 2 week antibiotic combination therapy to be effective similarly in severity levels as well as extension types of UC patients. Moreover, steroid-dependent UC patients were less effective by the treatments compared with refractory to or non-steroid UC patients.

Extraintestinal manifestations of inflammatory bowel disease and intestinal tuberculosis: Frequency and relation with disease phenotype.

Extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD), as well as intestinal tuberculosis (ITB) from Asia, are underreported. We, therefore, describe the prevalence of EIMs in Indian IBD and ITB patients and study their relationship with disease extent and severity in IBD. This retrospective single-center study included all IBD and ITB patients evaluated from January 2005 to July 2012. Disease profile and frequencies of arthropathies (peripheral and central) and ocular (episcleritis, iritis/uveitis), oral (aphthous stomatitis), skin (erythema nodosum, pyoderma gangrenosum, psoriasis), hepatobiliary (primary sclerosing cholangitis), and thromboembolic manifestations were analyzed. Of 1,652 patients (1146 UC, 303 CD, 203 ITB), frequency of any EIM was 33.2%, 38.3%, and 14.3% in UC, CD, and ITB patients, respectively. Thromboembolism was more common among UC patients with pancolitis than proctitis (p < 0.001) and left-sided colitis (p = 0.02). Primary sclerosing cholangitis was seen in 0.4% UC patients. Steroid-dependent UC patients had higher frequency of any EIM, peripheral arthropathy, or thromboembolism than patients with no or infrequent steroid requirement (p < 0.05). Peripheral arthropathy (p = 0.02), erythema nodosum (p = 0.01), and aphthous stomatitis (p = 0.004) were more common with CD than with UC patients. Patients with colonic CD had higher frequency of peripheral arthropathy, any EIM, and multiple EIMs than ileal or ileocolonic disease (p < 0.05). Relative to ITB, CD patients had higher frequencies of peripheral arthropathy (p < 0.001), aphthous stomatitis (p = 0.01), any EIM (p < 0.001), and multiple EIMs (p < 0.001). In Indian IBD and ITB patients, EIMs appear to be related to disease severity in UC and disease location in CD and are significantly more common in CD than in ITB. Overall prevalence of EIMs in these patients is similar to that of the West.

Infliximab in Steroid-dependent Ulcerative Colitis

Up to 20% of patients with ulcerative colitis (UC) become steroid-dependent during their course. Thiopurines are recommended in steroid-dependent UC, but their efficacy is debated. Data exploring the use of infliximab in these patients are scarce. Aims of this study were to evaluate the effectiveness of infliximab in steroid-dependent UC and identify predictors of steroid-free remission, mucosal healing (MH), and colectomy. Steroid-dependent UC patients were enrolled and intentionally treated with infliximab. The prospectively designed analyses evaluated (1) steroid-free clinical remission at 6 and 12 months, (2) steroid-free clinical remission and MH at 12 months, and (3) colectomy within 12 months. One hundred and twenty-six active steroid-dependent UC patients were studied. Of the 126 patients, 36 patients were retrospectively included and 90 patients prospectively enrolled. Steroid-free remission was 53% and 47% at 6 and 12 months, respectively. Predictors of steroid-free remission at 6 and 12 months were thiopurine-naive status (hazard ratio [HR], 2.5 and HR, 2.8, respectively) and combination therapy (HR, 2.1 and HR, 2.2, respectively). At 12 months, 32% were in steroid-free remission and MH. Thiopurine-naive status predicted steroid-free remission and MH (odds ratio, 3.6). C-reactive protein drop to normal after infliximab induction was predictive of steroid-free remission at 6 (HR, 5.9) and 12 months (HR, 4.6) and steroid-free remission and MH at 12 months (odds ratio, 6.0). Twelve patients underwent colectomy after a median of 4.7 months. Steroid sparing significantly reduced the risk of colectomy within 12 months (HR, 0.14). Infliximab seems effective in steroid-dependent UC. Thiopurine-naive status and combination therapy significantly increase the rate of steroid-free remission up to 12 months.

Letter: surgery for ulcerative colitis mostly follows anti‐TNF drugs ‐ a new ‘therapeutic package’?

We read with interest Nørgård et al. article ‘Pre-operative use of anti-TNF-α agents and the risk of post-operative complications in patients with ulcerative colitis – a nationwide cohort study’.1 This is a very interesting study, with a good design and including a high number of patients. The results confirm the feelings of most gastroenterologists about the absence of more post-operative complications in ulcerative colitis (UC) patients who received anti-TNF before a colectomy. Undoubtedly, these results will help in the future when we -gastroenterologists- have to ‘convince’ surgeons, classically more sceptical in this issue due to the results of previous studies.2, 3 What we find rather interesting in the article is the progressive increase in the use of anti-TNFs before colectomy, with nearly 90% of patients treated with these drugs in the last 3 years. Anti-TNF indications in UC are progressively increasing; nowadays they are not only used for steroid-refractory UC 4 but also for some patients after ciclosporin failure.5 Anti-TNF drugs are commonly used in steroid-dependent UC patients after thiopurines failure,6, 7 and if in this indication anti-TNFs do not work, the next step should be colectomy.8 We think that in the near future most UC patients who are going to be colectomised, perhaps with the exception of those having a very severe flare or those having high-grade dysplasia, could have previously been treated with anti-TNF drugs. Nevertheless, in a slightly more distant future, the increased use of anti-TNF drugs before colectomy may not be as beneficial. It is known that about 30% of UC patients who undergo a colectomy will develop pouchitis.9 In recent years, anti-TNF drugs have been more commonly used for the treatment of chronic refractory pouchitis, but in a recent Spanish (GETECCU) multicenter study we have observed that patients who had received infliximab before colectomy, when treated for chronic refractory pouchitis with the same drug, had a poorer response and developed more adverse events.10 Declaration of personal and funding interests: None.

Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry

Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index ≤2 together with complete steroid withdrawal and response as a decrease of ≥3 from the baseline score. A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the Adacolumn™ system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. In clinical practice, apheresis allows long-term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines.

Antibiotic Combination Therapy for Steroid Withdrawal in Steroid-Dependent Ulcerative Colitis

Background and Aim: Immunosuppressive drugs are recommended for use as replacements of steroid therapy in sustaining remission of steroid-dependent ulcerative colitis (UC). However, discontinuation of these therapeutic agents leads to a high relapse, and their long-term administration has not been proven safe. A newly introduced antibiotic combination therapy led to improvement and remission of active UC. The aim of this study is to examine whether this new therapy can replace immunosuppressive agents and allow discontinuation of steroids in steroid-dependent UC remission. Methods: 48 patients with steroid-dependent UC were recruited for a 2-week treatment with amoxicillin, tetracycline, and metronidazole (ATM). Examination of clinical symptoms, endoscopy, and histological evaluation were performed before and 6 and 12 months after treatment. Results: The proportion of patients who showed clinical improvement at 6 and 12 months after treatment was 54.2% (26/48) and 75.0% (36/48), respectively. The rate of clinical remission at 6 and 12 months was 31.3% (15/48) and 37.5% (18/48), respectively. Steroid withdrawal was attained in 64.6% (31/48) and 70.8% (34/48) of patients at 6 and 12 months, respectively. Endoscopic improvement was detected in 56.3% (27/48), and histological improvement was detected in 52.1% (25/48) at the final observation point for each patient. Conclusion: The triple antibiotic therapy resulted in improvement, remission, and steroid withdrawal in steroid-dependent UC patients.

Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis – a review of three clinical trials

Importance of the field: As the pathogenesis of ulcerative colitis (UC) is unknown, a causative therapy is lacking. Therefore, some UC patients suffer from disease activity despite symptomatic anti-inflammatory treatment strategies. We claim that reduction of phosphatidylcholine (PC) in colonic mucus impairs the mucosal barrier and, thus, causes attacks of the commensal bacterial flora to induce colitis. Thus, mucus PC substitution could provide a causal therapy for UC.Areas covered in this review: A delayed released oral PC preparation (rPC) was found to substitute for the lack of PC in rectal mucus. In non-steroid-treated active UC, 53% of rPC-treated patients reached remission compared with 10% of placebo patients (p < 0.001). In a second trial with chronic-active, steroid-dependent UC patients, steroid withdrawal with a concomitant achievement of remission (CAI ≤ 3) or clinical response (≥ 50% CAI improvement) was reached in 15 rPC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002).What the reader will gain: The concept that missing PC in colonic mucus is the main pathogenetic factor for development of UC. PC can be substituted by rPC, which cures the disease in the majority of patients.Take home message: rPC is, to our knowledge, the first causative therapeutic option for patients with UC.

Phosphatidylcholine (Lecithin) and the Mucus Layer: Evidence of Therapeutic Efficacy in Ulcerative Colitis?

Colonic mucus protects against attacks from bacteria in stool. One component of mucus is phosphatidylcholine (PC) which is thought to be arranged as continuous lamellar layer in the apical mucus and to be responsible for establishing a protective hydrophobic surface. This ‘intestinal surfactant’ plays a key role in mucosal defense. Thus, a defective PC layer contributes to the development of inflammation. Analysis of rectoscopically acquired mucus aliquots revealed a 70% decrease in PC content in ulcerative colitis (UC) compared to Crohn´s disease (CD) and healthy controls – independent of disease activity. Accordingly, we propose that lack of mucus PC is a key pathogenetic factor in UC. In clinical studies a delayed-release oral PC preparation (rPC) was found to substitute the lack of PC in rectal mucus. Indeed, in non-steroid-treated active UC, 53% of rPC patients reached remission [clinical activity index (CAI) ≤3] compared to 10% of placebo patients (p ≤ 0.001). Endoscopic and histologic findings improved concomitantly. A second trial with 60 chronic-active, steroid-dependent UC patients was conducted to test for steroid-sparing effects. Complete steroid withdrawal with a concomitant achievement of remission (CAI ≤3) or clinical response (≧50% CAI improvement) was reached in 15 PC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). In conclusion, intrinsic reduction of PC (lecithin) in colonic mucus may be a key pathogenetic feature of UC. Topical supplement of PC by a delayed-released oral PC preparation is effective in resolving inflammatory activity of UC and may develop to a first-choice therapy for this disease.

Newly Developed Antibiotic Combination Therapy for Ulcerative Colitis: A Double-Blind Placebo-Controlled Multicenter Trial

Fusobacterium varium may contribute to ulcerative colitis (UC). We conducted a double-blind placebo-controlled multicenter trial to determine whether antibiotic combination therapy induces and/or maintains remission of active UC. Patients with chronic mild-to-severe relapsing UC were randomly assigned to oral amoxicillin 1500 mg/day, tetracycline 1500 mg/day, and metronidazole 750 mg/day, vs. placebo, for 2 weeks, and then followed up. The primary study end point was clinical response (Mayo score at 3 months after treatment completion) and secondary end points were clinical and endoscopic score improvements at 12 months. Anti-F. varium antibodies were measured by enzyme-linked immunosorbent assay. Treatment and placebo groups each had 105 subjects. At the primary end point, response rates were significantly greater with antibiotics than with placebo (44.8 vs. 22.8%, P=0.0011). Endoscopic scores significantly improved at 3 months (P=0.002 vs. placebo). Remission rates were 19.0% (antibiotics) vs. 15.8% (placebo) at 3 months (P=0.59). At the secondary end point, response rates were significantly greater with antibiotics than with placebo (49.5 vs. 21.8%, respectively, P<0.0001). Endoscopic scores were significantly improved at 12 months after antibiotic treatment (P=0.002 vs. placebo). Remission rates had improved to 26.7% with antibiotics vs. 14.9% for placebo, at 12 months (P=0.041). F. varium antibody titers decreased in responders but not in nonresponders, and more in the antibiotic than in the placebo group. More pretreatment steroid-dependent UC patients discontinued corticosteroids after treatment completion (6 months: 28.6 vs. 11.8%, respectively, P=0.046; 9 months: 34.7 vs. 13.7%, respectively, P=0.019; and 12 months: 34.7 vs. 13.7%, respectively, P=0.019). These effects were greater in the subanalysis of the active group (Mayo scores of 6-12) than in that of total cases (0-12). No serious drug-related toxicities occurred. The 2-week triple antibiotic therapy produced improvement, remission, and steroid withdrawal in active UC more effectively than a placebo.

Azathioprine maintains long-term steroid-free remission through 3 years in patients with steroid-dependent ulcerative colitis†

Studies assessing the efficacy of azathioprine (AZA) in steroid-dependent ulcerative colitis (SD-UC) are scarce. The purpose of this trial was to explore the efficacy of AZA in maintaining steroid-free remission in SD-UC patients and the factors associated with sustained response. In this observational cohort study, 42 subjects with SD-UC were recruited for AZA therapy during a 3-year period. AZA was adjusted for a target dose of 2-3 mg/kg/day. Steroid therapy was tapered off following a standardized regimen. The primary endpoint was the annual rate of steroid-free response to AZA. Secondary endpoints included clinical recurrence, yearly steroid dose, and safety of treatment. On an intention-to-treat basis, the proportion of patients remaining in steroid-free remission at 12, 24, and 36 months was 0.55, 0.52, and 0.45, respectively. A significant decrease in the flare-ups rate and in requirement for steroids were observed during 3 years on AZA compared with the previous year (P = 0.000 for both). Patients with and without sustained response were comparable according to demographics, extent of disease, dose of AZA, steroids, and 5-aminosalicylate (5-ASA) use. Only disease duration <36 months was associated with off-steroids remission (P = 0.02, odds ratio [OR] 3.12, 95% confidence interval [CI] 1.89-7.64). The AZA benefit-risk profile was favorable. In this open-label observational trial AZA showed sustained efficacy for maintenance of clinical remission off steroids and steroid sparing through 3 years of therapy in SD-UC. Patients with earlier UC are those who most probably will have sustained steroid-free remission at the end of 12 months while on AZA.

Granulocytapheresis in Paediatric IBD

Introduction: Selective Leukocyte Adsorptive Apheresis has proved its efficacy in adult inflammatory bowel disease (IBD), mainly in steroid-dependant or steroid-refractory Ulcerative Colitis. Granulocyte-monocyte apheresis is carried out through a direct blood perfusion system with a 335 mL capacity column filled with 220 g of cellulose diacetate beads (Adacolumn, JIMRO, Takasaki, Japan) that selectively adsorb circulating granulocytes and monocytes/macrophages. Objective: We present our results of granulocytapheresis on safety, tolerability and efficacy in a group of paediatric IBD patients followed up for one year. Material and Methods: Steroid-refractory and steroid-dependent ulcerative colitis patients and Crohn's disease patients with steroid-dependence or unresponsive to conventional treatments, aged between 11 and 18 years, with a mild-moderate flare-up (as defined by the modified Truelove index for UC and PCDAI for CD), were eligible. Nine patients (6 boys, 3 girls) entered our study, 5 steroid-dependent UC patients and 4 CD patients without sustained remission with different treatments (enteral nutrition, steroids, immunomodulators, infliximab) Mean age at inclusion was 13 years, 9 months and mean disease duration prior to inclusion had been 29 months. Granulocytapheresis consisted on 5 one hour length Adacolum sessions, one per week, for 5 consecutive weeks. Patients were followed for 52 weeks. In each visit, clinical symptoms, inflammatory markers and activity scores were evaluated. Results: In the UC group, 3/5 patients were in remission after 5 sessions (week 6). These 3 patients could taper off their steroid daily dose after 2 or 3 sessions. All of them maintained remission after 52 weeks without steroids. Other treatments (5-ASA, AZA) could also be stopped. In the CD group, 2 patients achieved clinical remission after 5 sessions (week 6) and another one did it later on the follow-up (week 17). One of the patients with an early response and the one with the late response maintained remission at the end of the study. No important side-effects due to the granulocytapheresis were observed and the technique was well tolerated by all our patients. Conclusions: Granulocytapheresis has shown its efficacy in our paediatric IBD patients. This is a very promising therapy especially in the paediatric age because of its safety, its steroid-sparing effect and its good tolerance. Certain aspects of this technique have to be further evaluated as its use in earlier stages of the disease seems to be more effective.

P0680 LEUKOCITE ADSORPTIVE APHERESIS IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE: SAFETY, TOLERANCE AND PRELIMINARY DATA OF EFFICACY

Introduction: Granulocytapheresis has proved its efficacy in adult IBD(1).Granulocytemonocyte(GM) apheresis is carried out with a column filled with cellulose diacetate beads (Adacolumn, Japan Immunoreseach Laboratories, Takasaki, Japan) that adsorb circulating GM. Reduction of activated GM and its immunomodulatory effect(2) results in alleviation of inflammation and promotes remission. No severe side-effects have been reported. Methods: These are the preliminary data of a multicenter pilot study on efficacy, safety and tolerance of Granulocytapheresis in paediatric IBD. Steroid-refractory and steroid-dependent ulcerative colitis patients and Crohn’s disease patients unresponsive to conventional treatments, aged 12–18 years (weigth >30kgs), are eligible. Granulocytapheresis is performed as previously described (1). Results: Patient 1: 15 year-old boy, with active ileocolic Crohn’s disease and perianal fistula for two years. Previous treatments: enteral nutrition,5-ASA,azathioprine, antibiotics,infliximab. PCDAI before apheresis: 35. Sessions were well tolerated. No complications nor side effects owing to apheresis. 3 weeks after last session, he is in remission(PCDAI:5). No gastrointestinal symptoms, mild perianal disease and decreased inflammation markers. He has gained 4.8 kgs in two months. Patient 2: 14 year-old girl. Stricturing ileo-colic Crohn’s disease since 9 years of age without response to enteral nutrition,5-ASA, azathioprine, infliximab. PCDAI before apheresis: 52’5. Sessions well tolerated, no complications nor side-effects. No remission of her moderate flare-up (PCDAI30), no changes in inflammatory markers. Due to persistence of her symptoms, methrotexate treatment was begun. Conclusion: Granulocytapheresis is a safe and well tolerated treatment in paediatric IBD. We have not seen any complication nor side-effect due to the technique in our two patients. We hope to reach conclusions on its efficacy once our study is finished.