Ulcerative Colitis: Sands BE

Sands BE, Cuffari C, Katz J, Kugathasan S, Onken J, Vitek C, Orenstein W. · Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Inflamm Bowel Dis. · Pubmed #15472534 No free full text.

Abstract: During the past 2 decades, medical therapy for Crohn's disease (CD) and ulcerative colitis (UC) has grown to incorporate a variety of immunesuppressing agents. At the same time, basic insights into the aberrant mucosal immune response underlying inflammatory bowel disease (IBD) have expanded dramatically. The interplay of host susceptibility to infection and the safety and efficacy of immunization for vaccine-preventable diseases has been explored in other immune-mediated disease states but only rarely in IBD. The purpose of this review is to formulate best-practice recommendations for immunization in children and adults with IBD by considering the effects of the IBD disease state and its treatments on both the safety and efficacy of immunization. To do so, we first considered the routine recommendations for immunization of children, adults and distinct populations at increased risk for vaccine-preventable disease. Because it was rarely possible to examine direct data on safety and efficacy of immunization in IBD populations, we relied to a large extent upon extrapolation from similar populations and from knowledge of basic mechanisms. The literature suggests that efficacy of immunization may be diminished in some patients whose immune status is compromised by immune suppression. However, except for live agent vaccines, most immunizations may be safely administered to patients with IBD even when immune compromised. Conversely, protection against vaccine-preventable illness may be of even greater benefit to those at risk for morbid or lethal complications of infections because of an immune compromised state. We conclude that for most patients with IBD, recommendations for immunization do not deviate from recommended schedules for the general population.

Abreu MT, Plevy S, Sands BE, Weinstein R. · Inflammatory Bowel Disease Center, New York, NY, USA. · J Clin Gastroenterol. · Pubmed #18090155 No free full text.

Abstract: The etiology of inflammatory bowel disease (IBD) is not completely understood, thus current therapies have been empirical and directed at treating symptoms rather than addressing the cause. In IBD, the overexpression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, leads to a persistent intestinal inflammatory response that damages the intestinal mucosa. Recent advances in pharmacologic therapies that target specific cytokines, chemokines, and adhesion molecules have proved successful in alleviating symptoms for some patients. There are 2 selective adsorption apheresis devices that remove leukocytes from whole blood, which are currently available in Japan and Europe-the Cellsorba leukocytapheresis column and the Adacolumn adsorptive extracorporeal granulocyte/monocyte apheresis device. The purported mechanisms of action of these devices have been extensively reviewed and are believed to exert an immunomodulatory and/or anti-inflammatory effect on patients with systemic inflammatory disease. The clinical trials presented here indicate that selective leukocyte apheresis effectively removes activated granulocytes and monocytes/macrophages from peripheral blood while maintaining an excellent safety profile. Despite these findings, large controlled trials of selective leukocyte apheresis in the treatment of IBD are needed to determine the true efficacy of this approach.

Sands BE, Kaplan GG. · Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Diseases, and MGH Crohn's and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. · J Clin Pharmacol. · Pubmed #17567930 No free full text.

Abstract: Standard of care for ulcerative colitis involves long-term pharmacotherapy or colectomy. Approximately 20% to 30% of patients eventually require a colectomy because patients either do not respond or cannot tolerate the currently available pharmacotherapies. Advances in our knowledge of the pathophysiology of ulcerative colitis have highlighted the importance of cytokines such as tumor necrosis factor alpha (TNFalpha) in the inflammatory process. TNFalpha is a proinflammatory mediator that plays an integral role in the pathogenesis of inflammatory bowel disease. In addition, mounting evidence indicates a genetic association between TNFalpha and ulcerative colitis. Furthermore, increased TNFalpha levels have been demonstrated in studies of patients with ulcerative colitis. TNFalpha is likely an important component in the pathophysiology of ulcerative colitis, and thus agents targeting TNFalpha in ulcerative colitis have been studied. Recent randomized controlled trials have confirmed that biologic anti-TNFalpha therapy is effective in ulcerative colitis. Soluble TNFalpha receptors or biologic agents that suppress or inhibit TNFalpha production may also show therapeutic promise.

Sands BE. · MGH Crohn's and Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge Street, 9th Floor, Boston, MA 02114, USA. · J Gastroenterol. · Pubmed #17322989 No free full text.

Abstract: Crohn's disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are largely diseases of the twentieth century, and are associated with the rise of modern, Westernized industrial society. Although the causes of these diseases remain incompletely understood, the prevailing model is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in the genetically susceptible host. A review of the past and present of these diseases shows that detailed description preceded more fundamental elucidation of the disease processes. Working out the details of disease pathogenesis, in turn, has yielded dividends in more focused and effective therapy for IBD. This article highlights the key descriptions of the past, and the pivotal findings of current studies in disease pathogenesis and its connection to medical therapy. Future directions in the IBD will likely explicate the inhomogeneous causes of these diseases, with implications for individualized therapy.

Sands BE. · MGH Crohn's and Colitis Center, Massachusetts General and Gastrointestinal Unit Hospital, 165 Cambridge St, 9th Floor, Boston, MA 02114, USA. · Gut. · Pubmed #16531519 links to  free full text

Abstract: Immunosuppressive drugs have become a mainstay of therapy for the inflammatory bowel diseases. Although robust evidence exists in support of the use of these drugs in Crohn's disease, a close evaluation of the available data in ulcerative colitis reveals a much weaker evidence base. In particular, randomised controlled trials of azathioprine, the most commonly used immunosuppressive agent, do not provide rich evidence of efficacy whereas observational cohorts suggest this agent is effective, particularly in patients with relapsing disease who require corticosteroids. Ciclosporin is also effective in the most refractory cases but its efficacy needs to be carefully weighed against the possibility of rare but life threatening complications. Although the evidence base in support of immunosuppressive drugs in ulcerative colitis is not as strong as in Crohn's disease, these agents clearly have a role in the treatment of this disease.

Isaacs KL, Lewis JD, Sandborn WJ, Sands BE, Targan SR. · University of North Carolina, Chapel Hill, North Carolina, USA. · Inflamm Bowel Dis. · Pubmed #16254481 No free full text.

Abstract: Inflammatory bowel diseases (IBD) encompass Crohn's disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen-associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T-cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD.

Siegel CA, Sands BE. · Gastrointestinal Unit and MGH Crohn's and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · Aliment Pharmacol Ther. · Pubmed #15963074 links to  free full text

Abstract: Azathioprine, mercaptopurine, methotrexate, ciclosporin and tacrolimus all have their respective niches in the treatment of inflammatory bowel disease. These immunomodulators are potent and effective medications; however, they potentially have serious toxicity. To maximize benefit and minimize risk, clinicians must understand the mechanism of action, appropriate indications, range of toxicity and proper dosing of these medications. Furthermore, once initiating therapy, patients need to be monitored appropriately for evidence of efficacy and toxicity. This review includes the rationale behind recommendations for the management and monitoring of patients using immunomodulators. For the purine antagonists--azathioprine and mercaptopurine--the evidence for utility of thiopurine methyltransferase testing and mercaptopurine metabolite monitoring is addressed. The roles of liver biopsy and screening for methylenetetrahydrofolate reductase mutations in patients taking methotrexate are reviewed. With appropriate monitoring, the calcineurin inhibitors--ciclosporin and tacrolimus--can be used safely and effectively. Immunomodulators are important agents for the treatment of Crohn's disease and ulcerative colitis, and prescribing clinicians should be comfortable recognizing both their value and their limitations.

Sands BE. · Gastrointestinal Unit and Center for the Study of IBD, Massachusetts General Hospital, 55 Fruit Street, GRJ 7, Boston, Massachusetts 02114 USA. · Gastroenterology. · Pubmed #15168364 No free full text.

This publication has no abstract.

Sands BE. · Gastrointestinal Unit and Center for the Study of IBD, Massachusetts General Hospital, Boston, USA. · Acta Gastroenterol Belg. · Pubmed #11475137 No free full text.

Abstract: Biological therapies are being increasingly investigated for the treatment of inflammatory bowel disease. However, a great deal more study has been devoted to studies of Crohn's disease rather than ulcerative colitis. Ulcerative colitis, like Crohn's disease, represents an area of high clinical need, particularly for those patients who have disease inadequately responsive to corticosteroids and 5-aminosalicylates. The distinct anatomic distribution of inflammation in ulcerative colitis represents an important model for study, with the entire involved mucosa entirely accessible to endoscopy. In addition, there is an opportunity for local delivery of biologic agents in left-sided disease. Distinct pathogenetic factors in ulcerative colitis raise the possibility of therapies quite different from those used in Crohn's disease. This work describes the current state of knowledge regarding biological therapy in ulcerative colitis. The role of probiotic therapy, and studies of cytokine-directed therapies, therapies targeting adhesion and recruitment, and restitution and repair are described.

Sands BE. · Gastrointestinal Unit and Center for the Study of IBD, Massachusetts General Hospital, Boston, USA. · Acta Gastroenterol Belg. · Pubmed #11475127 No free full text.

Abstract: Biological agents for the treatment of IBD are the result of both the explosion of knowledge precipitated by the techniques of molecular biology, and by the ability to use these same techniques to produce agents. Thus, there has been a greatly facilitated translation of basic knowledge into clinical therapy. An astounding number of biologic agents are currently in development for the treatment of IBD and other immune-mediated conditions. These include native microbiologic preparations isolated for beneficial properties, recombinant cytokines and anticytokines, monoclonal antibodies, antisense oligonucleotides, and in the future, somatic gene therapy. This work seeks to describe the principles and techniques of biologic agent development, as well as prime sites of action targeted by these agents. Recent advances in the techniques of molecular biology have made possible unprecedented progress in the treatment of many conditions. The techniques of molecular biology have provided new methods of drug discovery and at the same time have elucidated new therapeutic targets. Most notable has been the progress made in the treatment of chronic inflammatory and immune mediated conditions, including inflammatory bowel disease. This paper is intended to highlight the methodological principles behind biologic agents, methods of discovery and production, and to highlight potential therapeutic targets for these new agents.

Sands BE. · Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA. · Gastroenterology. · Pubmed #10868899 No free full text.

Abstract: In the last decade, substantial gains have been made in the treatment of inflammatory bowel disease (IBD). Refinements in drug formulation have provided the ability to target distinct sites of delivery, enhancing the safety and efficacy of older agents. Immunosuppressive agents beyond corticosteroids have assumed a routine part in the care of patients with IBD. Moreover, as the century closes, we stand at the threshold of unprecedented advances in knowledge of the pathogenesis of ulcerative colitis and Crohn's disease. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This review covers agents currently used in the treatment of IBD and seeks to provide an overview of emerging therapies.

Sands BE, Sandborn WJ, Wolf DC, Katz S, Safdi M, Schwartz DA, Hanauer SB. · Gastrointestinal Unit and MGH Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA 02114, USA. · J Clin Gastroenterol. · Pubmed #16825929 No free full text.

Abstract: GOALS: Two uncontrolled, multicenter feasibility studies evaluated safety and pilot efficacy of selective granulocyte and monocyte adsorption apheresis (GMA) with the Adacolumn Apheresis System for treatment of moderate-to-severe ulcerative colitis (UC) and Crohn disease (CD) patients refractory/intolerant to conventional pharmacologic therapy. BACKGROUND: Patients with UC and CD, characterized by elevations in peripheral blood granulocytes, monocytes/macrophages, and proinflammatory mediators, may benefit from reductions in activated granulocytes and monocytes by selective apheresis. METHODS: Patients underwent weekly Adacolumn sessions for 5 weeks. Pilot efficacy assessments used disease activity index (DAI) for UC (0-12) or CD activity index (CDAI; 0-600) for CD. RESULTS: Eleven of 15 UC patients completed all 5 treatments. Mean DAI scores fell from 8.4+/-1.3 (baseline) to 5.2+/-2.9 (week 7). Five patients had DAI reductions of > or = 3 points at week 7. Fourteen of 15 CD patients completed all 5 treatments. Mean CDAI scores fell from 308.0+/-76.5 (baseline) to 200.6+/-117.4 (week 7). Nine CD patients responded (CDAI reductions > or = 70 points) at week 7. Remission (CDAI score < or = 150 at week 7) was observed in 6 patients. There were no device-related serious adverse effects. CONCLUSIONS: Treatment with Adacolumn may be feasible and effective in patients with moderate-to-severe refractory inflammatory bowel disease. Larger sham-controlled studies are ongoing.

Sandborn WJ, Sands BE, Wolf DC, Valentine JF, Safdi M, Katz S, Isaacs KL, Wruble LD, Katz J, Present DH, Loftus EV, Graeme-Cook F, Odenheimer DJ, Hanauer SB. · Mayo Clinic, Rochester, MN, USA. · Aliment Pharmacol Ther. · Pubmed #12786629 links to  free full text

Abstract: BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, Targan SR, Podolsky DK. · Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston 02114, USA. · Inflamm Bowel Dis. · Pubmed #11383595 No free full text.

Abstract: We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Sands BE, LeLeiko N, Shah SA, Bright R, Grabert S. · Harvard Medical School, USA. · Med Health R I. · Pubmed #19385383 No free full text.

This publication has no abstract.

Lam MY, Lee H, Bright R, Korzenik JR, Sands BE. · MGH Crohn's & Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · Inflamm Bowel Dis. · Pubmed #19023897 No free full text.

Abstract: BACKGROUND: The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a written, self-administered instrument measuring quality of life in IBD. We assessed the validity of an interactive voice response system (IVRS) as a new mode of administering the SIBDQ. METHODS: An IVRS was designed using prerecorded questions to collect data via touchtone telephone. Subjects with Crohn's disease (CD) or ulcerative colitis (UC) were randomized into 2 groups with different orders of administration: written, self-administered followed by IVRS (S-I) or IVRS followed by written, self-administered (I-S). Half of the S-I group was also randomized to receive a second IVRS. Sixty-four subjects were studied: 30 in S-I, 34 in I-S. RESULTS: The mean SIBDQ scores were not different between written and IVRS modes (P = 0.26) with r = 0.93. IVRS scores were lower in active than inactive CD (36.1 +/- 9.6 versus 54.7 +/- 8.6, P < 0.001) and lower in active than inactive UC (40.8 +/- 9.6 versus 59.8 +/- 10.0, P < 0.001). Mean scores correlated highly with disease activity indices, and were not different between first and second IVRS administrations (P = 0.85) with r = 0.92. IVRS had excellent internal consistency (Cronbach alpha = 0.90). CONCLUSIONS: IVRS administration of the SIBDQ yields results similar to written self-administration, with excellent procedural validity, test-retest reliability, and internal consistency.

Sands BE. · MGH Crohn's and Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge St., 9th Floor, Boston, MA 02114, USA. · J Gastrointest Surg. · Pubmed #18766416 No free full text.

Abstract: Fulminant colitis is an important clinical challenge despite great progress in its management over the decades. Corticosteroids greatly reduced mortality and colectomy rates, however, case fatality rates remain at roughly 2%. The goal of medical therapy is to prevent colectomy while avoiding complications that may lead to death or worsen the outcome of colectomy, if this cannot be avoided. In addition to corticosteroids, cyclosporine and infliximab have been used in the setting of severe colitis. Rescue therapy with cyclosporine must be followed by maintenance therapy with a thiopurine agent if successful remission is to be maintained durably. Rescue therapy with infliximab may be followed by maintenance therapy with the same agent, or in some cases, by a thiopurine agent. Both cyclosporine and infliximab may be associated with increased risks, such as neurotoxicity in the case of cyclosporine, or opportunistic or serious infection in the setting of immune suppression from either agent. In either case, it is critical to avoid excessive prolongation of unsuccessful medical therapy if optimal surgical outcomes are to be achieved. A great deal of judgment is needed to guide the timing of colectomy, but it is clear that mortality increases as the time to colectomy is prolonged.

Kunitake H, Hodin R, Shellito PC, Sands BE, Korzenik J, Bordeianou L. · Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, ACC 460, Boston, MA 02114, USA. · J Gastrointest Surg. · Pubmed #18709514 No free full text.

Abstract: PURPOSE: The impact of infliximab (IFX) on postoperative complications in surgical patients with Crohn's disease (CD) and ulcerative colitis (UC) is unclear. We examined a large patient cohort to clarify whether a relationship exists between IFX and postoperative complications. METHODS: A total of 413 consecutive patients--188 (45.5%) with suspected CD, 156 (37.8%) with UC, and 69 (16.7%) with indeterminate colitis--underwent abdominal surgery at the Massachusetts General Hospital between January 1993 and June 2007. One hundred one (24.5%) had received preoperative IFX < or = 12 weeks before surgery. These patients were compared to those who did not receive IFX with respect to demographics, comorbidities, presence of preoperative infections, steroid use, and nutritional status. We then compared the cumulative rate of complications for each group, which included deaths, anastomotic leak, infection, thrombotic complications, prolonged ileus/small bowel obstruction, cardiac, and hepatorenal complications. Potential risk factors for infectious complications including preexisting infection, pathological diagnosis, and steroid or IFX exposure were further evaluated using logistic regression analysis. RESULTS: Patients were similar with respect to gender (IFX = 40.6% men vs. non-IFX = 51.9%, p = 0.06), age (36.1 years vs. 37.8, p = 0.43), Charlson Comorbidity Index (5.3 vs. 5.7, p = 0.25), concomitant steroids (75.3% vs. 76.9%, p = 0.79), preoperative albumin level (3.3 vs. 3.2, p = 0.36), and rate of emergent surgery (3.0% vs. 3.5%, p = 1.00). IFX patients had higher rates of CD (56.4% vs. 41.9%, p = 0.02), concomitant azathioprine/6-mercaptopurine use (34.6% vs. 16.6%, p < 0.0001), and lower rates of intra-abdominal abscess (3.9% vs. 11%, p < 0.05). After surgery, the two groups had similar rates of death (2% vs. 0.3% p = 0.09), anastomotic leak (3.0% vs. 2.9%, p = 0.97), cumulative infections (5.97% vs. 10.1%, p = 1), thrombotic complications (3.6% vs. 3.0%, p = 0.06), prolonged ileus/small bowel obstructions (3.9 vs. 2.8, p = 0.59), cardiac complications (1% vs. 0.6%, p = 0.42), and hepatic or renal complications (1.0 vs. 0.6% p = 0.72). A logistic regression model was then created to assess the impact of IFX, as well as other potential risk factors, on the rates of cumulative postoperative infections. We found that steroids (odds ratio [OR] = 1.2, p = 0.74), IFX (OR 2.5, p = 0.14), preoperative diagnosis of CD (OR = 0.7, p = 0.63) or UC (OR = 0.6, p = 0.48), and preoperative infection (OR = 1.2, p = 0.76) did not affect rates of clinically important postoperative infections. CONCLUSIONS: Preoperative IFX was not associated with an increased rate of cumulative postoperative complications.

Sands BE, Sandborn WJ, Feagan B, Löfberg R, Hibi T, Wang T, Gustofson LM, Wong CJ, Vandervoort MK, Hanauer S, Anonymous00103. · MGH Crohn's & Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Gastroenterology. · Pubmed #18602921 No free full text.

Abstract: BACKGROUND & AIMS: Activated granulocytes and monocytes/macrophages are implicated in the pathogenesis of ulcerative colitis. Open-label studies and clinical experience in Japan and Europe have suggested that granulocyte/monocyte apheresis is safe and effective in treating ulcerative colitis. METHODS: We evaluated the efficacy of granulocyte/monocyte apheresis in a randomized, double-blind, sham-controlled trial in patients with active moderate-to-severe ulcerative colitis (Mayo score 6-11) in community-based and tertiary care centers. As intervention, we used granulocyte/monocyte apheresis with the Adacolumn Apheresis System (JIMRO, Ltd, Takasaki, Japan) or sham apheresis in a 2:1 ratio for 9 weeks of treatment in a North American pivotal study (N = 168) and in a smaller, companion study of identical design conducted in Europe and Japan (N = 47). RESULTS: In the pivotal study, clinical remission rates (Mayo score 0-2, with scores of 0 on rectal bleeding and 0 or 1 on endoscopic examination) were 17% and 11% for the granulocyte/monocyte apheresis (n = 112)- and sham-treatment groups, respectively (n = 56; P = .361). Clinical response (Mayo score reduction of >/=3 points from baseline) was observed in 44% and 39% of patients, respectively (P = .620). Similar changes were observed for the apheresis- and sham-treatment groups for endoscopic remission and response, and changes in Mayo and quality-of-life scores. The companion study and pooled data from both studies also yielded similar results. CONCLUSIONS: In this study, granulocyte/monocyte apheresis was well tolerated but did not demonstrate efficacy for induction of clinical remission or response in patients with moderate-to-severe ulcerative colitis.

Lewis JD, Lichtenstein GR, Deren JJ, Sands BE, Hanauer SB, Katz JA, Lashner B, Present DH, Chuai S, Ellenberg JH, Nessel L, Wu GD, Anonymous00007. · Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Gastroenterology. · Pubmed #18325386 links to  free full text

Abstract: BACKGROUND & AIMS: Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score </=2), endoscopic remission, and quality of life were secondary outcomes. RESULTS: After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (P = .04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare. CONCLUSIONS: Rosiglitazone was efficacious in the treatment of mild to moderately active UC.

Kaplan GG, McCarthy EP, Ayanian JZ, Korzenik J, Hodin R, Sands BE. · Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada. · Gastroenterology. · Pubmed #18242604 No free full text.

Abstract: BACKGROUND & AIMS: Postoperative morbidity and mortality following a colectomy for ulcerative colitis (UC) has been primarily reported from tertiary care referral centers that perform a high volume of operations; however, the postoperative outcomes among nonselected hospitals are not known. We set out to evaluate postoperative morbidity and mortality using a nationally representative database and to determine the factors that influenced outcomes. METHODS: We analyzed the 1995-2005 Nationwide Inpatient Sample to identify 7108 discharges for UC patients who underwent a total abdominal colectomy. The effects of hospital volume on postoperative morbidity and mortality were evaluated in logistic regression models adjusting for demographic and clinical factors. RESULTS: Postoperative mortality and morbidity rates were 2.3% and 30.8%, respectively. Most operations were performed in low-volume hospitals that had an increased risk of death (adjusted odds ratio [aOR], 2.42; 95% confidence interval [CI]: 1.26-4.63). In-hospital mortality was increased in patients who were admitted emergently (aOR, 5.40; 95% CI: 3.48-8.40), aged 60-80 years (aOR, 8.70; 95% CI: 3.30-22.92), and those with Medicaid (aOR, 4.29; 95% CI: 2.13-8.66). Emergently admitted UC patients whose surgery was performed 6 days after their admission had significantly increased likelihood of in-hospital death (aOR, 2.12; 95% CI: 1.13-3.97). CONCLUSIONS: Postoperative mortality was lowest in hospitals that performed the highest volume of operations. Increasing the proportion of total colectomies performed in high-volume hospitals may improve clinical outcomes for patients with UC.

Ooi CJ, Sands BE. · Center for the Study of Inflammatory Bowel Diseases, Gastrointestinal Unit, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA. · Curr Opin Gastroenterol. · Pubmed #17023961 No free full text.

Abstract: Advances in the treatment of ulcerative colitis have continued to focus on improved local delivery of existing agents, such as 5-aminosalicylate and corticosteroids, and on novel immunosuppressive agents. Although newer preparations of 5-aminosalicylate continue to provide incremental benefits in safety, tolerance, and efficacy, there is a growing understanding of the limits of benefit from increasing doses. Knowledge of the safety of these agents, particularly in regard to their use in pregnancy, continues to expand. Novel corticosteroids are used in much of the world for the treatment of ulcerative colitis, with the exception of the United States, with anticipated benefits in safety but little additional therapeutic benefit. Innovative use of oral emulsion preparations of cyclosporine has been reported in the treatment of ulcerative colitis and adds to the growing body of literature on the efficacy of cyclosporine in severe disease. Relatively limited experience with other immunosuppressive agents, such as tacrolimus, has been reported. The role of antibiotics in the treatment of ulcerative colitis has continued to present controversy.

Sands BE, Kilgore KM, Bloomfeld RS, Sandborn WJ. · Gastrointestinal Unit and MGH Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA. · J Clin Gastroenterol. · Pubmed #16917398 No free full text.

Abstract: BACKGROUND AND AIMS: Ulcerative colitis treatment is based largely on anatomic extent of inflammation and severity. Clinical severity is designated by the terms mild, moderate, or severe. The aims of this study are to assess consistency between: (1) community physicians and established treatment guidelines in their respective operational definitions of severity and (2) clinical severity ratings and resulting treatment. METHODS: Medical records of 411 patients who were successfully treated with mesalamine delayed release tablets without requiring steroids were reviewed. Data recorded included the prescribed dose of mesalamine, clinical symptoms, and physician's global assessment (PGA). RESULTS: Physicians were moderately consistent with the American College of Gastroenterology Guidelines in their assignments of PGA (kappa=0.57, P<0.001). An alternative decision rule, which deviated from the guidelines by placing a higher proportion of patients in the mild category, yielded a significantly higher kappa of 0.69 (P<0.001). The associations between severity measures and mesalamine dose yielded tau statistics of 0.13, 0.16, and 0.14 (all P<0.001), respectively for PGA, number of stools per day and percentage of stools with blood. CONCLUSIONS: Ulcerative colitis treatment quality may be enhanced by promoting a more consistent terminology for disease severity and reducing the unexplained variation in treatment dosing.

Siegel CA, Sands BE. · Section of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Dartmouth Medical School, Lebanon, NH, and Gastrointestinal Unit, MGH Crohn's and Colitis Center, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. · Inflamm Bowel Dis. · Pubmed #16775493 No free full text.

Abstract: BACKGROUND: Few data exist regarding exposures associated with colorectal cancer (CRC) in patients with Crohn's colitis. The aim of this study was to identify exposures that alter the risk of CRC in patients with Crohn's colitis. METHODS: The Research Patient Database Registry at Massachusetts General Hospital was searched to identify cases and controls. Cases had a confirmed diagnosis of Crohn's disease involving at least one third of the colon and a confirmed diagnosis of colorectal adenocarcinoma. Matched controls were randomly chosen from the same source population. Paired univariate analysis was performed to develop an odds ratio (OR) for each exposure. RESULTS: Twenty-seven patients were found to have Crohn's colitis and CRC. Colonoscopy performed for screening or surveillance was associated with an OR of 0.21 (95% CI 0.04-0.77; P=0.02). Nonsignificant trends for a protective effect included prior appendectomy (OR 0.30; 95% CI 0.05-1.17; P=0.10) and regular 5-aminosalicylate use (OR 0.30; 95% CI 0.05-1.17; P=0.10). Smoking history was associated with a 4-fold-increased risk for CRC, but this was not statistically significant (OR 4.00; 95% CI 0.80-38.67; P=0.11). CONCLUSIONS: We found that having a colonoscopy for an indication of surveillance or screening is associated with decreased risk of CRC in the setting of Crohn's colitis. These data underscore the importance of CRC surveillance for Crohn's colitis in addition to ulcerative colitis and should prompt further study in this area.

Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. · University Hospital Gasthuisberg, Leuven, Belgium. · N Engl J Med. · Pubmed #16339095 links to  free full text

Abstract: BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)