Ulcerative Colitis: Ardizzone S

Ardizzone S, Puttini PS, Cassinotti A, Porro GB. · Chair of Gastroenterology, "L. Sacco" University Hospital, Milan, Italy. · Dig Liver Dis. · Pubmed #18598997 No free full text.

Abstract: Inflammatory bowel disease (IBD) is associated with a variety of extraintestinal manifestations (EIMs) that may produce greater morbidity than the underlying intestinal disease and may even be the initial presenting symptoms of the IBD. As many as 36% of patients with IBD have at least one EIM. Some are more common related to active colitis (joint, skin, ocular, and oral manifestations). Others are especially seen with small bowel dysfunction (cholelithiasis, nephrolithiasis, and obstructive uropathy), and some are nonspecific disorders (osteoporosis, hepatobiliary disease, and amyloidosis). Patients with perianal Crohn's disease are at higher risk for developing EIMs than other IBD patients. Also the presence of one EIM appears to confer a higher likelihood of developing other manifestations than would be expected by chance alone. The identified pathogenetic autoimmune mechanisms include genetic susceptibility antigenic display of autoantigen, aberrant self-recognition, and immunopathogenetic autoantibodies against organ-specific cellular antigen(s) shared by colon and extra-colonic organs. Microbes may play an important role, probably by molecular mimicry. Early recognition of these extraintestinal manifestations should help guide therapy that will reduce overall morbidity in affected patients. This paper reviews the diagnosis, therapy and management of the more common EIMs.

Bianchi Porro G, Cassinotti A, Ferrara E, Maconi G, Ardizzone S. · Department of Clinical Science, Chair of Gastroenterology, L Sacco University Hospital, Milan, Italy. · Aliment Pharmacol Ther. · Pubmed #17767462 No free full text.

Abstract: BACKGROUND: Approximately 20% of patients with ulcerative colitis have a chronic active disease often requiring several courses of systemic steroids in order to achieve remission, but followed by relapse of symptoms during steroid tapering or soon after their discontinuation. Although short term control of symptoms can be achieved with steroid treatment, this pattern of drug response, known as steroid-dependency, leads to important complications of the treatment, while a significant proportion of patients requires colectomy. AIM: To review the studies currently available specifically evaluating the management of steroid-dependent ulcerative colitis. RESULTS: The clinical and biological mechanisms of steroid-dependency are not well understood compared with those determining steroid-refractoriness. Very few evidence-based data are available concerning the management of patients with steroid-dependent ulcerative colitis. The therapeutic role of aminosalicylates, thiopurines, methotrexate, infliximab, leukocyte apheresis and other drugs in the treatment of steroid-dependent ulcerative colitis are evaluated. CONCLUSIONS: Outcomes of studies in steroid-refractory patients may not be applicable to steroid-dependency. Trials are needed to define the correct approaches and new strategies to ameliorate the therapy of steroid-dependent ulcerative colitis.

Cassinotti A, Massari A, Ferrara E, Greco S, Bosani M, Ardizzone S, Bianchi Porro G. · Department of Clinical Science, Gastroenterology Unit, L. Sacco University Hospital, Via G.B. Grassi 74, 20157, Milan, Italy. · Eur J Clin Pharmacol. · Pubmed #17598094 No free full text.

Abstract: CASE REPORT: We present the case of a 52-year-old man with steroid-dependent ulcerative colitis, needing immunosuppressive therapy with azathioprine. The drug had been started 3 years earlier, but stopped after a few months because the patient reported palpitations, lipothymia, nausea and vomiting. Given the continued steroid-dependent ulcerative colitis and the lack of clinical documentation about a reaction with a dubious relationship to azathioprine, we decided to rechallenge the patient with the drug under clinical monitoring and after informed consent. After starting 50 mg of azathioprine, the patient showed general malaise, nausea and vomiting. An ECG showed atrial fibrillation, and the patient reported that the symptoms were similar to those previously experienced. DISCUSSION: We have found two other cases of similar onset of atrial fibrillation after azathioprine use, although some confounding elements in these episodes make the possible causal relationship between the drug and this adverse event uncertain.

Baratti C, De Simone A, Grassi C, Righi I, Massara PP, Pizzi M, Ferla F, Sposato J, Ardizzone S, Trabucchi E. · Università degli Studi di Milano, U.O.C. Chirurgia Generale I e. · Ann Ital Chir. · Pubmed #17139960 No free full text.

Abstract: The development of clinical and histopathological criteria for the diagnosis of Crohn's disease (CD) and ulcerative colitis (UC), pushed the scientists to identify a new category: the indeterminate colitis (CI). This term is used when definitive diagnosis of UC or CD has not been made by colonoscopy, colonic biopsy or colectomy. The distinction between these forms has major implications including the choice of medical treatment, timing of surgery, prognosis and disease course. The role of surgery in inflammatory bowel disease differs between the three main forms: in CD is primarily to treat complications of the disease process; in UC surgery is curative for intestinal manifestations and nearly eliminates the risk of future malignancy; in IC is actually discussed: the current guidelines identify in surgery the best treatment for fulminate disease, intractability of disease symptoms or failure of medical therapy. Although there is a few number of studies in the literature, selective criteria for the diagnosis and successful treatment must be revisited. The term CI should be used as a pending tray diagnosis, representing diagnostic inadequacy and not as specific nosological entity. Evidence emerging from the studies of serological markers (ASCA and P-ANCA) suggests that a subgroup of patients initially diagnosed as IC maybe identified as a separate group, and so they need a specific treatment for their disease.

Ardizzone S, Bianchi Porro G. · Chair of Gastroenterology, L. Sacco University Hospital, Milan, Italy. · Drugs. · Pubmed #16266194 No free full text.

Abstract: Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.

Caprilli R, Angelucci E, Cocco A, Viscido A, Annese V, Ardizzone S, Biancone L, Castiglione F, Cottone M, Meucci G, Paoluzi P, Papi C, Sturniolo GC, Vecchi M. · Promoter Centre, GI Unit, Department of Clinical Science, University of Rome 'La Sapienza', Viale del Policlinico 155, 00161 Rome, Italy. · Dig Liver Dis. · Pubmed #15893279 No free full text.

Abstract: INTRODUCTION: Despite the explosion of biological therapies, the old immunosuppressants continue to play a pivotal role in the management of inflammatory bowel diseases. AIM: To assess the appropriateness of immunosuppressants-azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, tacrolimus (FK506), mycophenolate mofetil and thalidomide-in the treatment of inflammatory bowel disease by using RAND/University of California Appropriateness Method. METHODS: The RAND method consists of a combination of evidence from the literature and experts' opinions. Appropriateness has been defined to mean that the expected health benefit exceeds the expected negative consequences by a sufficiently wide margin. A panel of 10 experts from the Italian Group for Inflammatory Bowel Disease has rated, in two rounds, on a scale from 1 to 9, the appropriateness of each indication selected by the Promoter Centre, on the basis of their own clinical experience. An indication was considered appropriate if the median of the panelists' ratings fell within the area 7-9, inappropriate in the area 1-3 and uncertain in the area 4-6. A total of 2781 indications were grouped into 13 categories (mild to moderate Crohn's disease; severe Crohn's disease; fistulizing Crohn's disease; steroid-dependant and -resistant Crohn's disease; maintenance of remission induced by medical treatment in Crohn's disease; maintenance of remission induced by surgery in Crohn's disease; mild to moderate ulcerative colitis; severe ulcerative colitis; steroid-dependant and -resistant ulcerative colitis; maintenance of remission induced by medical treatment in ulcerative colitis; extra-intestinal manifestations in inflammatory bowel disease; pregnancy and inflammatory bowel disease; azathioprine-resistant or -intolerant inflammatory bowel disease patients). RESULTS: Of the 2781 scenarios, 212 (7.6%) were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. The most relevant results were: in steroid-dependant or -resistant Crohn's disease, azathioprine, 6-mercaptopurine and methotrexate were defined as appropriate in 25 (86.2%) and 14 (48.3%) of the 29 scenarios respectively; in Crohn's disease, azathioprine and 6-mercaptopurine were defined as appropriate combined with Infliximab (bridge therapy); in steroid-dependant or -resistant ulcerative colitis, azathioprine and 6-mercaptopurine were defined as appropriate in 45 (77.6%) out of 58 scenarios, while methotrexate was defined appropriate only after previous azathioprine failure; in severe ulcerative colitis, cyclosporine A was defined as appropriate only after previous failure with steroids; in azathioprine-intolerant or -resistant inflammatory bowel disease patients, methotrexate was appropriate in 20 (66.7%) out of 30 scenarios; it is inappropriate to stop azathioprine treatment before conception in the presence of active disease. The use of FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate or uncertain. CONCLUSIONS: Results of this study show that only azathioprine, 6-mercaptopurine and methotrexate are appropriate in the treatment of inflammatory bowel diseases. Cyclosporine A was found to be appropriate only in severe ulcerative colitis after the failure of steroids. FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate but experience with these agents is somewhat limited.

Ardizzone S, Bianchi Porro G. · L. Sacco University Hospital, Milan, Italy. · J Intern Med. · Pubmed #12472908 No free full text.

Abstract: Despite all the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we do not know the cause. Some of the most recently available data have been discussed here and yet it is now becoming increasingly accepted that immunogenetics play an important role in the predisposition, modulation, and perpetuation of IBD. The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. The role of intestinal milium, and enteric flora in particular, appears to be of greater significance than previously held. A review is made of the main areas of research exploring the mechanisms more intimately associated with the development of IBD, providing advances in the agents currently used, and identifying a host of new therapeutic agents potentially interacting with or interrupting specific targets in the genesis of IBD.

Ardizzone S, Bianchi Porro G. · Department of Gastroenterology, L. Sacco University Hospital, Milan, Italy. · Drug Saf. · Pubmed #12113642 No free full text.

Abstract: This article reviews the clinical pharmacology, adverse events, and comparative tolerability of the drugs commonly available for treating ulcerative colitis. Synthetic glucocorticoids are the most commonly used conventional corticosteroids in the treatment of ulcerative colitis. Corticosteroids can be expected to impact on every organ system and most metabolic activities of the body. Suppression of the hypothalamic-pituitary-adrenal axis is common, but reversible, with conventional corticosteroids, but not with newer topically-acting corticosteroids. A serious complication of corticosteroids in children is growth retardation. The frequent adverse effects associated with the use of corticosteroids have prompted the development of a new group of rectal agents with equivalent efficacy and a more benign adverse event profile such as prednisolone metasulfobenzoate, fluticasone propionate, tixocortol pivalate, beclomethasone dipropionate and budesonide. The incidence of adverse effects related to the use of sulfasalazine (5-aminosalicylic acid plus sulfapyridine) is high and is dose related. The most frequently reported adverse effect is intolerance, not allergy, and relates to the sulfapyridine moiety correlating with the acetylator phenotype. Tolerance to 5-aminosalicylic acid by 80 to 90% of those patients allergic to, or intolerant of, sulfasalazine has given further evidence suggesting that the sulfa moiety is responsible for much of the toxicity of sulfasalazine. However, 10 to 20% of patients who are sulfasalazine intolerant have similar reactions to 5-aminosalicylic acid formulations, indicating that the 5-aminosalicylic acid moiety is responsible for adverse events in some patients taking sulfasalazine. Adverse effects resulting from treatment with azathioprine and mercaptopurine can be divided into two categories: allergic-type reactions that appear to be dose-independent and nonallergic-type reactions that are probably dose- and metabolism-dependent. It is well established now that genotype and thiopurine methyltransferase activity have an important impact on the rate of adverse effects during azathioprine or mercaptopurine therapy. Adverse effects resulting from high dose cyclosporin therapy for inflammatory bowel disease include: renal insufficiency, hypertension, opportunistic infections, seizures, paresthesias, tremor, headache, gingival hyperplasia, hypertrichosis, and anaphylaxis with intravenous cyclosporin. In contrast, the incidence of adverse events was relatively low when low-dose oral cyclosporin was used. The incidence of adverse events associated with any of the medications used in the treatment of ulcerative colitis is difficult to assess and it is therefore hard to make a comparative evaluation. The broadening of the drug regimen available to the clinician has advanced our knowledge about the disease, and further development of more effective, less toxic agents can be anticipated in the future.

Ardizzone S, Bollani S, Manzionna G, Bianchi Porro G. · Gastrointestinal Unit L. Sacco, University Hospital, Milan, Italy. · Eur J Gastroenterol Hepatol. · Pubmed #10495168 No free full text.

Abstract: The aetiology of inflammatory bowel disease remains unknown, but genetic, immuno-inflammatory, infectious, vascular and neural factors play an important role. All effective treatments in use today were introduced empirically and most have multiple action. Targeted therapy is very attractive, either with cell and gene therapy or by using specific cytokine inhibitors and inhibitory cytokines. The role of the intestinal milieu, and enteric flora in particular, appears to have a much greater significance than previously appreciated. The reduction of any changes leading to pro-coagulant activity may be a promising line of therapeutic investigation, and measures to reduce platelet aggregation and endothelial cell adhesiveness are examples of therapeutic potentials. Finally, there has been tangible demonstration of the ability of nerves to alter the inflammatory process which will lead to new therapeutic approaches in inflammatory bowel disease.

Paoluzi P, D'Albasio G, Pera A, Bianchi Porro G, Paoluzi OA, Pica R, Cottone M, Miglioli M, Prantera C, Sturniolo G, Ardizzone S. · Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy. · Dig Liver Dis. · Pubmed #12546514 No free full text.

Abstract: BACKGROUND: The association of oral 5-aminosalicylic acid (mesalazine) and enema is effective in treatment of mild-moderate forms of ulcerative colitis. However no study has been aimed at determining optimal duration of this association in active ulcerative colitis. AIM: To determine whether longer duration of therapy: 1. increases the rate of patients achieving remission, and 2. reduces relapse rate during the maintenance period in patients in remission. PATIENTS AND METHODS: A total of 149 patients, (89 male, 60 female), were randomly assigned to a regimen with 5-aminosalicylic acid tablets 2.4 g/day associated with 5-aminosalycilic enema 2 g/day for a 4-week (n = 73) or 8-week regimen (n = 76). After this acute therapy, patients were submitted to clinical, endoscopic and histological examinations and those in remission were assigned to a follow-up (maintenance) period with oral mesalazine alone at a dosage of 1.2 g/day. A clinical visit, including laboratory tests, at 6 months and an endoscopic-histological control at 12 months were carried out to exclude symptoms and endoscopic-histological signs of activity. Relapse of disease, i.e., presence of clinical symptoms or abnormal laboratory tests, was confirmed by endoscopy and histology. RESULTS: At end of acute phase, clinical, endoscopic and histological remission was comparable in the two groups: 42/76 (55%), in the 4-week, and 47/73 patients (64%), in the 8-week regimen. No difference was found stratifying patients according to extension of disease. Of these 89 patients in remission, 75 (34 from 4-week regimen; 41 from 8-week regimen) completed 12 months' follow-up. At end of follow-up, a similar percentage of patients in the 4-week regimen (50%) and 8-week regimen (51%) were still in remission. No significant difference between cumulative relapse rates of the two groups was found. Stratifying patients according to extension of disease, in the 8-week regimen group, those with left-sided colitis showed a higher remission rate than that of patients with diffuse colitis (66% versus 35%, p < 0.05). All regimens were well tolerated by most patients during the entire study period. CONCLUSIONS: An additional 4 weeks of topical treatment does not increase the remission rate in patients with mild-moderate active ulcerative colitis but seems to reduce the probability of relapse in patients with left-sided colitis.

Ardizzone S, Doldo P, Ranzi T, Sturniolo GC, Giglio LA, Annese V, D'Arienzo A, Gaia E, Gullini S, Riegler G, Valentini M, Massa P, Del Piano M, Rossini F, Guidetti CS, Pera A, Greinwald R, Bianchi Porro G. · L. Sacco University Hospital, Milan, Italy. · Ital J Gastroenterol Hepatol. · Pubmed #10730559 No free full text.

Abstract: BACKGROUND: Mesalazine enemas are of well proven efficacy for the topical treatment of distal ulcerative colitis. Although new rectal formulations of mesalazine are not expected to be superior in efficacy and tolerability to standard formulations, they may offer secondary advantages in terms of overall acceptability. AIM: To compare the efficacy, tolerability and overall acceptability of a new mesalazine rectal foam (Salofalk foam) with mesalazine enema in the treatment of active distal ulcerative colitis. PATIENTS AND METHODS: A multicentre study was carried out in patients with active proctitis, proctosigmoiditis and left-sided ulcerative colitis as evaluated by the Clinical Activity Index (CAI > or =4) and Endoscopic Index (EI > or =6). Patients were randomly assigned to receive, in open-label fashion, either mesalazine foam 2 g twice a day or mesalazine enema (2 g/60 ml twice a day) for 3 weeks. Patients who did not achieve remission (defined as CAI <4 and EI <6) after 3 weeks continued the study receiving the alternative galenic formulation for a further 3 weeks. RESULTS: A total of 195 patients were enrolled. Characteristics at baseline were similar except for concomitant therapy with oral 5-ASA products: during the 1st treatment phase, 41% of patients on enema received such treatment vs only 29% of those on foam. Patients with at least one post-treatment efficacy evaluation were included in the intent-to-treat analysis (n=89 foam, n=96 enema). After 3 weeks of treatment, 112 patients were in remission and only 59 patients entered the 2nd treatment phase thus providing data on acceptability. Remission was achieved after 3 weeks in 54% of patients treated with foam and in 67% of those treated with enema. The 90% confidence interval for the difference in remission rates was 0 to 24 and thus within the clinically acceptable range of therapeutic equivalence. At the end of the 2nd phase, 70% of patients switched to foam were in remission vs 65% to the enema. Two patients discontinued treatment with foam prematurely due to anal burning. No clinically important changes were seen in the laboratory tests. CONCLUSIONS: Salofalk foam and enema are equally effective for the treatment of proctitis, proctosigmoiditis and left-sided ulcerative colitis. The new foam preparation is as well tolerated and accepted as enemas and can be used as a therapeutic alternative to conventional mesalazine enema formulations.

Gionchetti P, Ardizzone S, Benvenuti ME, Bianchi Porro G, Biasco G, Cesari P, D'albasio G, De Franchis R, Monteleone G, Pallone F, Ranzi T, Trallori G, Valpiani D, Vecchi M, Campieri M. · University of Bologna, Italy. · Aliment Pharmacol Ther. · Pubmed #10102972 links to  free full text

Abstract: BACKGROUND: A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis. AIM: To evaluate the efficacy, safety and patient tolerability of mesalazine gel enema compared with mesalazine foam enema in the treatment of patients with acute left-sided ulcerative colitis. METHODS: In a randomized multicentre investigator-blind parallel group trial, 103 patients with mild to moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50 evaluable patients) and mesalazine 2 g foam enema (n = 53 evaluable patients) for 4 weeks. Clinical symptoms, endoscopic and histological findings were assessed at entry, 2 and 4 weeks. Patients' evaluation of treatment tolerability and acceptability was assessed at 2 and 4 weeks. RESULTS: After 4 weeks of treatment, clinical remission was achieved by 76% of mesalazine gel enema-treated patients and 69% of patients treated with mesalazine foam enema (P = 0.608). Endoscopic remission rates at week 4 were 51 and 52% for the mesalazine gel and foam enemas, respectively (P = 0.925). Histological remission was achieved by 30% of patients in both groups. Patients reported that the new mesalazine gel preparation was significantly better tolerated than the foam enema. Patients in the foam group had significantly more difficulty in retention (25% vs. 6%, P < 0.05), abdominal bloating (50% vs. 26%, P < 0.005) and discomfort during administration (48% vs. 26%, P < 0.05). CONCLUSION: The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema.

Ardizzone S, Petrillo M, Imbesi V, Cerutti R, Bollani S, Bianchi Porro G. · Gastrointestinal Unit, 'L. Sacco' Hospital, Milan, Italy. · Aliment Pharmacol Ther. · Pubmed #10102971 links to  free full text

Abstract: BACKGROUND: The efficacy of sulphasalazine and mesalazine in preventing relapse in patients with ulcerative colitis is well known. It is less clear how long such maintenance should be continued, and if the duration of disease remission is a factor that affects the risk of recurrence. AIM: To determine whether the duration of disease remission affects the relapse rate, by comparing the efficacy of a delayed-release mesalazine (Asacol, Bracco S.p.A., Milan, Italy) against placebo in patients with ulcerative colitis with short- and long-duration of disease remission. METHODS: 112 patients (66 male, 46 female, mean age 35 years), with intermittent chronic ulcerative colitis in clinical, endoscopic and histological remission with sulphasalazine or mesalazine for at least 1 year, were included in the study. Assuming that a lower duration of remission might be associated with a higher relapse rate, the patients were stratified according to the length of their disease remission, prior to randomization into Group A (Asacol 26, placebo 35) in remission from 1 to 2 years, or Group B (Asacol 28, placebo 23) in remission for over 2 years, median 4 years. Patients were treated daily with oral Asacol 1.2 g vs. placebo, for a follow-up period of 1 year. RESULTS: We employed an intention-to-treat analysis. In Group A, whilst no difference was found between the two treatments after 6 months, mesalazine was significantly more effective than placebo in preventing relapse at 12 months [Asacol 6/26 (23%), placebo 17/35 (49%), P = 0.035, 95% Cl: 48-2.3%]. In contrast, in Group B no statistically significant difference was observed between the two treatments, either at 6 or 12 months [Asacol 5/28 (18%), placebo 6/23 (26%), P = 0.35, 95% Cl: 31-14%] of follow-up. Patients in group B were older, and had the disease and remission duration for longer, than those in Group A. CONCLUSIONS: Mesalazine prophylaxis is necessary for the prevention of relapse by patients with ulcerative colitis in remission for less than 2 years, but this study casts doubt over whether continuous maintenance treatment is necessary in patients with prolonged clinical, endoscopic and histological remission, who are at very low risk of relapse.

Bourreille A, Ignjatovic A, Aabakken L, Loftus EV, Eliakim R, Pennazio M, Bouhnik Y, Seidman E, Keuchel M, Albert JG, Ardizzone S, Bar-Meir S, Bisschops R, Despott EJ, Fortun PF, Heuschkel R, Kammermeier J, Leighton JA, Mantzaris GJ, Moussata D, Lo S, Paulsen V, Panés J, Radford-Smith G, Reinisch W, Rondonotti E, Sanders DS, Swoger JM, Yamamoto H, Travis S, Colombel JF, Van Gossum A, Anonymous00249. · Institut des Maladies de l'Appareil Digestif, CHU, Université de Nantes, Nantes, France. · Endoscopy. · Pubmed #19588292 No free full text.

Abstract: Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world. Whereas ulcerative colitis is a chronic inflammatory condition causing diffuse and continuous mucosal inflammation of the colon, Crohn's disease is a heterogeneous entity comprised of several different phenotypes, but can affect the entire gastrointestinal tract. A change in diagnosis from Crohn's disease to ulcerative colitis during the first year of illness occurs in about 10 % - 15 % of cases. Inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis or Crohn's disease is termed IBD-unclassified (IBDU). The advent of capsule and both single- and double-balloon-assisted enteroscopy is revolutionizing small-bowel imaging and has major implications for diagnosis, classification, therapeutic decision making and outcomes in the management of IBD. The role of these investigations in the diagnosis and management of IBD, however, is unclear. This document sets out the current Consensus reached by a group of international experts in the fields of endoscopy and IBD at a meeting held in Brussels, 12-13th December 2008, organised jointly by the European Crohn's and Colitis Organisation (ECCO) and the Organisation Mondiale d'Endoscopie Digestive (OMED). The Consensus is grouped into seven sections: definitions and diagnosis; suspected Crohn's disease; established Crohn's disease; IBDU; ulcerative colitis (including ileal pouch-anal anastomosis [IPAA]); paediatric practice; and complications and unresolved questions. Consensus guideline statements are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not read in isolation.

Atzeni F, Ardizzone S, Bertani L, Antivalle M, Batticciotto A, Sarzi-Puttini P. · Rheumatology Unit, L Sacco University Hospital, Milano, Italy. · World J Gastroenterol. · Pubmed #19468996 links to  free full text

Abstract: Inflammatory bowel diseases (IBDs), particularly Crohn's disease (CD) and ulcerative colitis (UC), are associated with a variety of extra-intestinal manifestations (EIMs). About 36% of IBD patients have at least one EIM, which most frequently affect the joints, skin, eyes and the biliary tract. The EIMs associated with IBD have a negative impact on patients with UC and CD, and the resolution of most of them parallels that of the active IBD in terms of timing and required therapy; however, the clinical course of EIMs such as axial arthritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis is independent of IBD activity. The peripheral and axial arthritis associated with IBD have traditionally been treated with simple analgesics, non-steroidal anti-inflammatory drugs, steroids, sulfasalazine, methotrexate, local steroid injections and physiotherapy, but the introduction of biological response modifiers such as tumor necrosis factor-alpha blockers, has led to further improvements.

Ardizzone S, Cassinotti A, Trabattoni D, Manzionna G, Rainone V, Bevilacqua M, Massari A, Manes G, Maconi G, Clerici M, Bianchi Porro G. · Gastroenterology Unit, Department of Clinical Science, L. Sacco University Hospital, Milano, Italy. · Int J Immunopathol Pharmacol. · Pubmed #19309553 No free full text.

Abstract: Crohn's 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 4) 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-alpha, IFN-gamma) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-alpha 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-gamma (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-alpha 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.

Latiano A, Palmieri O, Valvano MR, D'Incà R, Cucchiara S, Riegler G, Staiano AM, Ardizzone S, Accomando S, de Angelis GL, Corritore G, Bossa F, Annese V. · Struttura Complessa di Endoscopia Digestiva, Ospedale Casa Sollievo della Sofferenza-I.R.C.C.S., Viale Cappuccini 1, San Giovanni Rotondo, Italy. · World J Gastroenterol. · Pubmed #18698678 links to  free full text

Abstract: AIM: To investigate gene variants in a large Italian inflammatory bowel disease (IBD) cohort, and to analyze the correlation of sub-phenotypes (including age at diagnosis) and epistatic interaction with other IBD genes. METHODS: Total of 763 patients with Crohn's disease (CD, 189 diagnosed at age < 19 years), 843 with ulcerative colitis (UC, 179 diagnosed < 19 years), 749 healthy controls, and 546 healthy parents (273 trios) were included in the study. The rs2241880 [autophagy-related 16-like 1 (ATG16L1)], rs11209026 and rs7517847 [interleukin 23 receptor (IL23R)], rs2066844, rs2066845, rs2066847 (CARD15), rs1050152 (OCTN1), and rs2631367 (OCTN2) gene variants were genotyped. RESULTS: The frequency of G allele of ATG16L1 SNP (Ala197Thr) was increased in patients with CD compared with controls (59% vs 54% respectively) (OR = 1.25, CI = 1.08-1.45, P = 0.003), but not in UC (55%). The frequency of A and G (minor) alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD (4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P < 0.01), compared with controls (6% and 38%, respectively). The A allele (but not G) was also reduced significantly in UC (4%, OR = 0.69, CI = 0.5-0.94, P = 0.019). No association was demonstrated with sub-phenotypes and interaction with CARD15, and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION: The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.

Manes G, Imbesi V, Ardizzone S, Cassinotti A, Bosani M, Massari A, Porro GB. · Department of Clinical Science, Chair and Department of Gastroenterology, L. Sacco University Hospital, Milano, Italy. · Inflamm Bowel Dis. · Pubmed #18314901 links to  free full text

Abstract: 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 endoscopist's management decisions based on patient's 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 adjunctive 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 endoscopist's 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.

Maconi G, Dominici R, Molteni M, Ardizzone S, Bosani M, Ferrara E, Gallus S, Panteghini M, Bianchi Porro G. · Department of Clinical Sciences, L Sacco University Hospital, Via GB Grassi, 74, Milan, Italy. · Dig Dis Sci. · Pubmed #17530399 No free full text.

Abstract: Pancreatic insufficiency (PI) may be an extraintestinal manifestation of inflammatory bowel diseases (IBD). We report the results of a cross-sectional study that was carried out to investigate both the prevalence of PI in IBD patients and its clinical course over a 6-month follow-up period. In total, 100 Crohn's disease (CD) patients, 100 ulcerative colitis (UC) patients, and 100 controls were screened for PI by the fecal elastase-1 (FE-1) test. The decision limits employed were: < or =200 microg/g stool for PI and < or =100 microg/g for severe PI. Patients with abnormal FE-1 values were re-tested after 6 months. Odds ratios (OR) for PI were estimated by unconditional logistic regression analysis. PI was found in 22 UC and 14 CD patients. The OR for the FE-1 test < or =200 microg/g was 10.5 [95% confidence interval (CI): 2.5-44.8] for IBD patients compared to the controls. The risk of PI was related to three or more bowel movements per day (OR = 25.0), the passage of loose stools (OR = 7.7), and previous surgery (OR = 3.7). At the 6-month follow-up, FE-1 values became normal in 24 patients and showed persistently low concentrations in 12. These patients had a larger number of bowel movements per day (OR = 5.4), previous surgery (OR = 5.7), and a longer duration of the disease (OR = 4.2). PI is frequently found in IBD patients, particularly in those with loose stools, a larger number of bowel movements/day and previous surgery. PI is reversible in most patients, and persistent PI is not associated with clinically active disease.

Parente F, Pastore L, Bargiggia S, Cucino C, Greco S, Molteni M, Ardizzone S, Porro GB, Sampietro GM, Giorgi R, Moretti R, Gallus S. · Gastrointestinal Unit, A. Manzoni Hospital, Lecco, and the Gastroenterology Unit, L. Sacco University Hospital, Milan, Italy. · Hepatology. · Pubmed #17464998 No free full text.

Abstract: The risk for gallstones (GD) in inflammatory bowel diseases and the factors responsible for this complication have not been well established. We studied the incidence of GD in a cohort of Crohn's disease (CD) and ulcerative colitis (UC) patients and investigated the related risk factors. A case-controlled study was carried out. The study population included 634 inflammatory bowel disease (IBD) patients (429 CD, 205 UC) and 634 age-matched, sex-matched, and body mass index (BMI)-matched controls free of GD at enrollment, who were followed for a mean of 7.2 years (range, 5-11 years).The incidence of GD was calculated by dividing the number of events per person-years of follow-up. Multivariate analysis was used to discriminate among the impact of different variables on the risk of developing GD. The incidence rates of GD were 14.35/1,000 persons/year in CD as compared with 7.75 in matched controls (P=0.012) and 7.48/1000 persons/year in UC patients as compared with 6.06 in matched-controls (P=0.38). Ileo-colonic CD location (OR, 2.14), disease duration>15 years (OR, 4.26), >3 clinical recurrences (OR, 8.07), ileal resection>30 cm (OR, 7.03), >3 hospitalizations (OR, 20.7), multiple TPN treatments (OR, 8.07), and long hospital stay (OR, 24.8) were significantly related to GD in CD patients. CONCLUSION: Only CD patients have a significantly higher risk of developing GD than well-matched hospital controls. Site of disease at diagnosis, lifetime surgery, extent of ileal resections, number of clinical recurrences, TPN, and the frequency and duration of hospitalizations are independently associated with GD.

Bianchi V, Maconi G, Ardizzone S, Colombo E, Ferrara E, Russo A, Tenchini ML, Porro GB. · Department of Biology and Genetics for Medical Sciences, University of Milan, Italy. · Eur J Gastroenterol Hepatol. · Pubmed #17301648 No free full text.

Abstract: AIMS: To confirm the prevalence of NOD2/CARD15 mutations in Italian inflammatory bowel disease patients and to define the role of the different mutations on Crohn's disease phenotype. PATIENTS AND METHODS: A total of 177 patients with Crohn's disease and 92 patients with ulcerative colitis and 164 control participants were investigated for the presence of Arg702Trp, Gly908Arg and Leu1007fsinsC NOD2/CARD15 mutations. Allele frequencies in Crohn's disease and ulcerative colitis patients were compared with those observed in the control population. Genotype-phenotype correlations with the major clinical features were also established and estimated risks (odds ratio with 95% confidence interval) for the mutations were calculated by logistic regression and multiple correspondent analysis. RESULTS: Gly908Arg and Leu1007fsinsC mutations were significantly more frequent in Crohn's disease patients compared with healthy controls (P<0.01 and <0.003 respectively). Indeed, using a logistic regression model adding terms for age (differently distributed between cases and controls) and sex, a significantly increased risk of having Crohn's disease compared with healthy controls was found for all NOD2 mutations: Leu1007fsinsC (odds ratio=7.35; 95% confidence interval: 1.73-31.3), Gly908Arg (odds ratio=5.70; 95% confidence interval: 1.37-23.7) and Arg702Trp (odds ratio=2.45; 95% confidence interval: 1.10-5.47). As far as the genotype-phenotype correlations are concerned, by multivariate conditional logistic regression methods, we found a significant association between Gly908Arg mutations and familial history of inflammatory bowel disease, between Leu1007fsinsC mutations and appendectomy and between Arg702Trp mutations and fibrostenotic phenotype of Crohn's disease. A nonsignificant association between Arg702Trp variants and ileal disease was also found (odds ratio=8, 95% confidence interval: 0.99-64.9). CONCLUSIONS: The results of the study confirm a significant association of CARD15 gene mutations in our Italian Crohn's disease population and the impact of different NOD2/CARD15 mutations on specific disease phenotypes.

Ardizzone S, Maconi G, Bianchi V, Russo A, Colombo E, Cassinotti A, Penati C, Tenchini ML, Bianchi Porro G. · Department of Gastroenterology L. Sacco University Hospital, University of Milan, Milan, Italy. · Inflamm Bowel Dis. · Pubmed #17260353 links to  free full text

Abstract: BACKGROUND: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. METHODS: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype-phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. RESULTS: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20-0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. CONCLUSIONS: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host-bacteria interactions and in the pathogenesis of IBD.

Furlan R, Ardizzone S, Palazzolo L, Rimoldi A, Perego F, Barbic F, Bevilacqua M, Vago L, Bianchi Porro G, Malliani A. · Unità Sincopi e Disturbi della Postura, Medicina Interna II, Ospedale L. Sacco, Università di Milano, Via G.B. Grassi 74, 20157 Milano, Italy. · Am J Physiol Regul Integr Comp Physiol. · Pubmed #16123227 No free full text.

Abstract: Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1) an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) and 2) a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure, and respiration were continuously recorded, and plasma catecholamine was evaluated both at rest and during a 75 degrees head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of low-frequency (LF) cardiac sympathetic (LF(RR); normalized units) and high-frequency (HF) parasympathetic (HF(RR); normalized units) modulation and sympathetic vasomotor control (LF systolic arterial pressure; LF(SAP)), obtained by spectrum analysis of the R-R interval and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8-wk transdermal clonidine (15 mg/wk, 9 subjects), or placebo (7 patients). An autonomic profile, Disease Activity Index (DAI), and endoscopic pattern were compared before and after clonidine/placebo. At rest, MSNA, heart rate (HR), LF(RR), LF/HF, and LF(SAP) were higher and HF(RR) was lower in patients than in controls. Tilt decreased HF(RR) and increased MSNA and LF(RR) less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF(RR), and increased HF(RR), whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.

Bargiggia S, Thorburn D, Anderloni A, Ardizzone S, Giorgi A, Bianchi Porro G, Parente F. · Academic Department of Gastroenterology, L.Sacco University Hospital, Milan, Italy. · Aliment Pharmacol Ther. · Pubmed #16091058 links to  free full text

Abstract: BACKGROUND: Hepatitis C virus infection is more common in patients with inflammatory bowel disease than in general population. Limited data are available as to the safety and efficacy of alpha-interferon therapy for chronic active hepatitis C in patients with concomitant inflammatory bowel disease. AIM: To evaluate the efficacy and safety of alpha-interferon monotherapy in patients with chronic active hepatitis C and inactive or mildly active inflammatory bowel disease. METHODS: A total of 513 consecutive inflammatory bowel disease patients at a single centre were tested for antibodies to hepatitis C virus (anti-hepatitis C virus) between 1995 and 2000. Twenty-one patients had detectable anti-hepatitis C virus Ab and were hepatitis C virus-RNA positive with histologically proved chronic active hepatitis. Each of these patients, whose inflammatory bowel disease was in clinical remission or mildly active, was sex- and age-matched to three controls with similar histological grade and stage of chronic hepatitis C virus but without inflammatory bowel disease; and all were treated with human leucocyte alpha-interferon 6 million units given thrice weekly for 12 months. Responses to treatment were classified as follows: complete response--persistently normal alanine aminotransferase and viral clearance (hepatitis C virus-RNA-ve) at the end-of-treatment, incomplete response--alanine aminotransferase normalization without viral clearance (hepatitis C virus-RNA+ve), and sustained response--alanine aminotransferase normalization and hepatitis C virus clearance 12 months after the end-of-treatment. RESULTS: Twenty-one patients with chronic active hepatitis C and inflammatory bowel disease (10 with Crohn's disease and 11 with ulcerative colitis) and 63 sex- and age-matched controls with chronic hepatitis C virus alone received alpha-interferon monotherapy. Response rates to interferon were similar for inflammatory bowel disease patients compared with controls [CR 42% vs. 35% and SR 24% vs. 18% (P, not significant), respectively]. None of the 21 inflammatory bowel disease patients had severe adverse effects and the mild ones observed were comparable with those seen in the control group. No patients developed an inflammatory bowel disease relapse during the interferon treatment period or in the 12 months thereafter. CONCLUSIONS: The biochemical and virological response to a 12-month human leucocyte alpha-interferon treatment in patients with chronic active hepatitis C are similar to that observed in matched controls with chronic hepatitis C virus without inflammatory bowel disease. Adverse effects are similar in both groups of patients and unrelated to the underlying inflammatory bowel condition. This provides hepatologists with evidence that alpha-interferon can be safely administered to patients with chronic hepatitis C virus and inflammatory bowel disease provided that the inflammatory bowel condition is in clinical remission.

Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. · Cattedra di Gastroenterologia, Azienda Ospedaliera "L Sacco", Polo Universitario, Via G.B. Grassi 74, 20157 Milano, Italy. · Gut. · Pubmed #15972298 links to  free full text

Abstract: BACKGROUND AND AIMS: There are limited evidence based data concerning the use of azathioprine in ulcerative colitis. We aimed to compare the efficacy of azathioprine and oral 5-aminosalicylic acid in inducing remission of steroid dependent ulcerative colitis. METHODS: Seventy two patients with steroid dependent ulcerative colitis were admitted to this investigator-blind study. Steroid dependence was defined as a requirement for steroid therapy > or =10 mg/day during the preceding six months, with at least two attempts to discontinue the medication. The disease had to be clinically and endoscopically active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive azathioprine 2 mg/kg/day or oral 5-aminosalicylic acid 3.2 g/day, for a six month follow up period. The outcome of the treatment was defined as (1) success, indicating induction of clinical and endoscopic remission and steroid discontinuation, or (2) failure, indicating the absence of clinical and endoscopic remission and therefore the need for at least one further cycle of systemic steroids to control symptoms, apart from the initial one, or colectomy. RESULTS: Significantly more patients in the azathioprine than in the 5-aminosalicylic acid group had clinical and endoscopic remission, and discontinued steroid therapy, both in the intention to treat (azathioprine v 5-aminosalicylic acid: 19/36 patients (53%) v 7/36 (21%); odds ratio (OR) 4.78 (95% confidence interval (CI) 1.57-14.5)) and per protocol (azathioprine v 5-aminosalicylic acid: 19/33 patients (58%) v 7/34 (21%); OR 5.26 (95% CI 1.59-18.1)) analysis. CONCLUSIONS: Azathioprine is significantly more effective than 5-aminosalicylic acid in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid dependent ulcerative colitis.