Ulcerative Colitis: Lewis JD

Lewis JD. · No affiliation provided · Gastroenterology. · Pubmed #14598269 No free full text.

This publication has no abstract.

Su C, Lewis JD, Goldberg B, Brensinger C, Lichtenstein GR. · Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania and University of Pennsylvania Presbyterian Medical Center, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Gastroenterology. · Pubmed #17258720 No free full text.

Abstract: BACKGROUND & AIMS: Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. METHODS: We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. RESULTS: Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%-18%; range, 0%-40%; median, 12%) and 28% (95% confidence interval, 23%-33%; range, 0%-67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. CONCLUSIONS: Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC.

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.

Judge TA, Lewis JD, Lichtenstein GR. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, PA 19104-4283, USA. · Gastrointest Endosc Clin N Am. · Pubmed #12486941 No free full text.

Abstract: Extracolonic malignancies are a relatively rare complication of inflammatory bowel disease. In contrast, colorectal cancer remains a major concern for patients with long-standing UC. The best available evidence suggests that patients with long-standing Crohn's colitis are at similar risk for colorectal cancer as those patients with long-standing UC. In patients with UC, the magnitude of this increased risk appears to be greater in patients with more extensive colonic involvement. It appears that the magnitude of this risk increases with increasing duration of disease, at least in UC. Whether this reflects the increased risk of cancer that occurs with the aging process or a separate phenomena distinct to UC is unclear. To date, the methods available to reduce the risk of cancer are less than optimal. Although surgical procedures eliminate the risk, the mental and physical sequelae of these procedures can be substantial. Surveillance with colonoscopic biopsies is likely effective in reducing although not eliminating the risk of colorectal cancer. Efforts to develop chemopreventative agents and improved surveillance methods remain areas of active investigation.

Su CG, Stein RB, Lewis JD, Lichtenstein GR. · Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. · Dig Liver Dis. · Pubmed #11057928 No free full text.

Abstract: The treatment of Crohn's disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators such as azathioprine and 6-mercaptopurine are an important class of medications used for the treatment of patients with inflammatory bowel disease. Controlled studies have demonstrated their efficacy in both induction and maintenance of remission in Crohn's disease, and similarly, for the induction and maintenance of remission in patients with ulcerative colitis. These agents have had an increasing importance in the management of steroid-resistant, steroid-dependent diseases, and fistulizing Crohn's disease. The primary limitations to these agents have been their slow onset of action and their side effect profile. Despite these limitations, these agents have demonstrated efficacy and have become paramount to the management of patients with these incurable potentially disabling disorders. The precise role of azathioprine/6-mercaptopurine, their limitations and their safety are reviewed in this paper.

Scotiniotis I, Lewis JD, Strom BL. · Division of Gastroenterology, University of Pennsylvania, Philadelphia, USA. · Curr Opin Oncol. · Pubmed #10416884 No free full text.

Abstract: Most of the major advances in the screening for gastrointestinal cancers this year were in the area of colorectal cancer screening. Currently, screening is recommended for the prevention of colorectal cancer in average and high-risk populations. For average risk populations, large randomized trials support the use of screening fecal occult blood testing, and case-control studies support the use of screening sigmoidoscopy. This year, several investigators have addressed issues related to the probability of identifying advanced lesions in the proximal colon following a positive screening flexible sigmoidoscopy. Similarly, two studies identified that villous histology in an index polyp was associated with an increased risk of recurrent colonic polyps. Additionally, two large trials provided new insight about the prevalence of mutations in the MLH1 or MSH2 mismatch-repair genes among patients with colorectal cancer. Lastly, a case-control study from Sweden provided the best evidence to date that surveillance colonoscopies for patients with long-standing ulcerative colitis may reduce cancer-related mortality. Although further work is needed, these studies have served to advance our knowledge of colorectal cancer screening substantially.

Lewis JD, Deren JJ, Lichtenstein GR. · Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, USA. · Gastroenterol Clin North Am. · Pubmed #10372277 No free full text.

Abstract: Patients with inflammatory bowel disease (IBD) are at increased risk for developing cancer of the gastrointestinal tract, particularly colorectal cancer. Because of the relative rarity of IBD in the general population, it has been difficult to quantify this risk. Efforts to reduce the risk have included both prophylactic surgery and endoscopic screening programs. Because of the potential impact on quality of life and life expectancy, the optimal strategy for reducing this risk has not been defined. This article reviews the current literature relating to the risk of cancer for patients with IBD and methods to reduce this risk.

Jones DT, Osterman MT, Bewtra M, Lewis JD. · School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6021, USA. · Am J Gastroenterol. · Pubmed #18844625 No free full text.

Abstract: OBJECTIVES: Active smoking has a well-documented role in the etiology of inflammatory bowel disease (IBD), but the role of passive smoking has been unclear. This meta-analysis examined the relationship between prenatal smoke exposure and childhood passive smoke exposure and the development of IBD. METHODS: We searched the MEDLINE and EMBASE databases to identify observational studies regarding the relationship between prenatal and/or childhood passive smoke exposure and the development of Crohn's disease (CD) and/or ulcerative colitis (UC). Pooled odds ratios (OR) were calculated for each relationship. RESULTS: A total of 534 and 699 potential studies were identified from the MEDLINE and EMBASE databases, respectively, of which 13 met all of our inclusion criteria. Overall, we did not observe a positive relationship between childhood passive smoke exposure and CD (OR 1.10, 95% confidence interval [CI] 0.92-1.30) or UC (OR 1.01, 95% CI 0.85-1.20). Likewise, we did not observe an association between prenatal smoke exposure and CD (OR 1.10, 95% CI 0.67-1.80), or prenatal smoke exposure and UC (OR 1.11, 95% CI 0.63-1.97). CONCLUSIONS: Our meta-analysis suggests that there is not a strong association between childhood passive smoke exposure and the development of CD. We found no evidence that childhood passive smoke exposure exerts a protective effect against UC, as is the case in active smoke exposure. The heterogeneity among the small number of studies limited the ability to draw conclusions about prenatal smoke exposure.

Herrinton LJ, Liu L, Lewis JD, Griffin PM, Allison J. · Division of Research, Kaiser Permanente Northern California, 2000 Broadway Avenue, Oakland, CA 94612, USA. · Am J Gastroenterol. · Pubmed #18796097 No free full text.

Abstract: OBJECTIVE: There are few estimates of the incidence and prevalence of inflammatory bowel disease in North American communities. We sought to estimate the incidence and prevalence of inflammatory bowel disease (IBD), including Crohn's disease (CD), and ulcerative colitis (UC), among 3.2 million members of Kaiser Permanente, Northern California, for the period 1996-2002. METHODS: All health plan members who had one or more diagnoses of CD (ICD-9 code 555) or UC (ICD-9 code 556) on computerized records during the period 1996-2002 and with at least 12 months of membership were identified as possible IBD cases (N = 12,059). We randomly sampled 24% of these for chart review to confirm the diagnosis and obtain the initial diagnosis date. Incidence rates and the point prevalence on December 31, 2002 were standardized to the 2000 U. S. Census. RESULTS: The annual incidence rate per 100,000 persons was 6.3 for CD (95% confidence interval [CI], 5.6-7.0) and 12.0 for UC (CI, 11.0-13.0). The point prevalence per 100,000 on December 31, 2002 was 96.3 for CD (95% CI, 89.6-103.0) and 155.8 for UC (95% CI, 146.6-164.9), increasing to 100.3 and 205.8 per 100,000, respectively, when hospital discharge data from 1985 to 1995 were included. The age-specific incidence of CD was bimodal, while UC incidence rose in early adulthood and remained elevated with advancing age. CONCLUSIONS: The incidence we estimated for CD was similar to the previous U. S. estimate. Our incidence estimate for UC was much higher than the previous U.S. estimate, but similar to that of recent Canadian and European studies. The prevalence we estimated for CD was somewhat lower than previous estimates.

Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. · Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. · Inflamm Bowel Dis. · Pubmed #18623174 No free full text.

Abstract: BACKGROUND: The Mayo score and a noninvasive 9-point partial Mayo score are used as outcome measures for clinical trials assessing therapy for ulcerative colitis (UC). There are limited data assessing what defines a clinically relevant change in these indices. We sought to assess what constitutes a clinically meaningful change in these indices using data from a recently completed placebo-controlled clinical trial. METHODS: In all, 105 patients were enrolled in a 12-week randomized, placebo-controlled trial assessing rosiglitazone for treatment of mild to moderate UC. We compared the change in the Mayo score, the partial Mayo score, and a 6-point score composed just of the stool frequency and bleeding components of the Mayo score to the patient's perception of disease activity at week 0 and week 12. Optimal cutpoints were calculated as the maximal product of sensitivity and specificity. RESULTS: Each index was strongly correlated with the patient's rating of disease activity at week 12 (Spearman correlations 0.61-0.71, P < 0.0001 for all correlations). The maximal product of sensitivity and specificity to identify patient reported improvement of disease activity was achieved using cutpoints for change of 2.5 for the Mayo score (sensitivity 88%, specificity 80%), 2.5 for the partial Mayo score (sensitivity 88%, specificity 87%), and 1.5 for the 6-point score (sensitivity 88%, specificity 80%). CONCLUSIONS: The partial Mayo score and the 6-point score composed solely of the stool frequency and bleeding components performed as well as the full Mayo score to identify patient perceived clinical response.

Lewis JD, Gelfand JM, Troxel AB, Forde KA, Newcomb C, Kim H, Margolis DJ, Strom BL. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Am J Gastroenterol. · Pubmed #18494836 No free full text.

Abstract: OBJECTIVE: This study examined whether treatment of Crohn's disease (CD) and ulcerative colitis (UC) with immunosuppressant medications was associated with an increased risk of death in the era prior to antitumor necrosis factor (TNF) therapies. DESIGN: This retrospective cohort study used data from the General Practice Research Database from 1987 to 1997. CD and UC patients were matched to controls on age, sex, and primary care practice. CD and UC patients were stratified according to whether they used immunosuppressant medications during follow-up. Cox proportional hazards models adjusted for comorbidities were used to define the relative hazard of death. Additional models examined the relative hazard of death with current use of corticosteroids or thiopurines. RESULTS: The cohort included 5,539 patients with CD, 8,910 patients with UC, and 41,624 controls. Patients with CD had an increased mortality (not immunosuppressant-treated CD hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.07-1.51; immunosuppressant-treated CD HR 2.44, 95% CI 1.84-3.25). Increased mortality was only observed among UC patients treated with immunosuppressant medications (HR 1.67, 95% CI 1.34-2.09). In both CD and UC, current corticosteroid therapy was associated with increased mortality (CD HR 2.48, 95% CI 1.85-3.31; UC HR 2.81, 95% CI 2.26-3.50). Current use of thiopurines was not associated with increased mortality (CD HR 0.83, 95% CI 0.37-1.86; UC HR 0.70, 95% CI 0.29-1.70). CONCLUSIONS: Patients treated with corticosteroids, but not thiopurines, are at increased risk of death, although this study could not clarify whether this was as a result of the medication or the underlying disease severity.

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.

Aberra FN, Stettler N, Brensinger C, Lichtenstein GR, Lewis JD. · Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Clin Gastroenterol Hepatol. · Pubmed #17627901 No free full text.

Abstract: BACKGROUND & AIMS: The primary aim of this study was to determine the incidence of active tuberculosis in an inflammatory bowel disease population compared with the general population before the availability of infliximab. METHODS: We performed a retrospective cohort study with the General Practice Research Database from January 1988-October 1997. Ulcerative colitis and Crohn's disease subjects with a minimum of 1 year of follow-up were matched to randomly selected subjects from the remaining population on year of birth (+/-5 years), sex, and primary care practice at ratio of 1:4. Active tuberculosis was determined by tuberculosis diagnostic codes. The incidence of active tuberculosis in the inflammatory bowel disease population and the relative risk for active tuberculosis in inflammatory bowel disease population compared with the general population were calculated. Multivariate logistic regression analysis was performed to adjust for confounders. RESULTS: There were 16,213 inflammatory bowel disease subjects and 66,512 control subjects. The annual incidence of active tuberculosis was 20/100,000 in inflammatory bowel disease subjects compared with 9/100,000 in control subjects, yielding an unadjusted relative risk for active tuberculosis of 2.36 (95% confidence interval, 1.17-4.74). Adjusting for confounders, corticosteroid use and smoking, the odds ratio of inflammatory bowel disease for active tuberculosis was 1.88 (95% confidence interval, 0.68-5.20). CONCLUSIONS: During the pre-infliximab era, inflammatory bowel disease subjects appeared to be at higher risk for active tuberculosis than the general population, with immunosuppressant medications likely the main reason for this increased risk.

Lichtenstein GR, Deren JJ, Katz S, Lewis JD, Kennedy AR, Ware JH. · Department of Medicine, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Dig Dis Sci. · Pubmed #17551835 No free full text.

Abstract: Bowman-Birk inhibitor concentrate (BBIC), a soy extract with high protease inhibitor activity, is efficacious in the treatment of colitis in mice and has been used in numerous clinical trials. A randomized, double blind, placebo-controlled trial was performed to investigate the safety and possible benefits of BBIC in patients with active ulcerative colitis. The Sutherland Disease Activity Index (SDAI) was used to assess disease activity, response (Index decrease > or = 3), and remission (Index < or = 1 with no rectal bleeding) in patients receiving 12 weeks of therapy. The Index scores of patients receiving BBIC decreased more than those of the patients receiving placebo (P = 0.067). Beneficial trends were observed in the rates of remission (P = 0.082) and clinical response (P = 0.22). No severe adverse events were observed. This trial suggests a potential benefit over placebo for both achieving clinical response and induction of remission in patients with active ulcerative colitis without apparent toxicity.

Bewtra M, Su C, Lewis JD. · Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Clin Gastroenterol Hepatol. · Pubmed #17382602 No free full text.

Abstract: BACKGROUND & AIMS: This study examined trends in hospitalization and surgery rates for inflammatory bowel disease (IBD) in the United States over a 14-year period. METHODS: We performed an analysis of secular trends of hospitalization and surgery rates from Crohn's disease (CD) and ulcerative colitis (UC) using the 1990 to 2003 National Hospital Discharge Survey data. The Spearman correlation coefficient was used to examine the association between calendar year and rates of hospitalization or bowel resection surgery. RESULTS: From 1990 to 2003, the hospitalization rates for patients with a primary diagnosis of IBD per 100,000 people ranged from 9.3 to 17.1 for CD and 8.2 to 12.4 for UC, with a significant trend for increasing hospitalization rates for CD (rho = .83, P = .0002) but not UC (rho = .06, P = .83). The annual rates of bowel resection surgeries per 100,000 people ranged from 2.8 to 5.0 for CD and from 1.6 to 3.4 for UC, with no significant trend for CD (rho = .30, P = .30) or UC (rho = -.31, P = .28). As expected, there was a significant trend for shorter hospitalizations for both CD (rho = -.98, P < .0001) and UC (rho = -.87, P < .0001). However, total hospital days did not change significantly for either CD or UC. CONCLUSIONS: Despite advances in therapy, IBD hospitalization and surgery rates in the United States have not decreased since 1990. Rather, there has been a significant increase in hospitalizations for CD, with stable rates of bowel resection surgery for CD and hospitalization and surgery for UC.

Gupta G, Lautenbach E, Lewis JD. · Center for Clinical Epidemiology and Biostatistics, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. · Clin Gastroenterol Hepatol. · Pubmed #17162240 No free full text.

Abstract: BACKGROUND & AIMS: An increased risk of herpes zoster in patients with inflammatory bowel disease (IBD) is hypothesized based on altered immune function, especially among patients receiving immunosuppressive medications. METHODS: We performed a retrospective cohort study and a retrospective nested case-control study using 1988-1997 data from the General Practice Research Database. In the cohort study, 7823 Crohn's disease (CD) and 11,930 ulcerative colitis (UC) patients were matched on age, sex, and primary care practice to 79,563 randomly selected controls without CD or UC. In the nested case-control study, 185 CD patients with zoster and 266 UC patients with zoster were matched on sex and year of birth to 1787 IBD patients without zoster. RESULTS: In the cohort study, the incidence of zoster was higher in patients with CD and UC compared with their matched controls (UC incidence rate ratio, 1.21; 95% confidence interval [CI], 1.05-1.40; CD incidence rate ratio, 1.61; 95% CI, 1.35-1.92). In the nested case-control study, receipt of a prescription for corticosteroids (adjusted odds ratio, 1.5; 95% CI, 1.1-2.2) or azathioprine/6-mercaptopurine (adjusted odds ratio, 3.1; 95% CI, 1.7-5.6) were both associated with zoster. CONCLUSIONS: Patients with IBD, especially those on immunosuppressive medications, are at higher risk for herpes zoster compared with the general population. Future studies should clarify the relative risk associated with anti-tumor necrosis factor alpha therapies and determine the use of the new zoster vaccine for patients with IBD.

Gupta G, Gelfand JM, Lewis JD. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. · Gastroenterology. · Pubmed #16143121 No free full text.

Abstract: BACKGROUND & AIMS: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor alpha therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions has not been established. METHODS: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn's disease and 12,185 ulcerative colitis patients were matched for age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS/D/ON could either precede or follow the IBD diagnosis. RESULTS: In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn's disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis (ulcerative colitis incidence rate ratio [IRR], 2.63; 95% confidence interval, 1.29-5.15; Crohn's disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS/D/ON was more prevalent in patients with Crohn's disease and ulcerative colitis compared with their matched controls (Crohn's disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio, 1.75; 95% confidence interval, 1.28-2.39). CONCLUSIONS: Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients. Future studies should clarify whether treatment with tumor necrosis factor alpha blockers results in further increased incidence of MS/D/ON among IBD patients.

Aberra FN, Brensinger CM, Bilker WB, Lichtenstein GR, Lewis JD. · Division of Gastroenterolgy, University of Pennsylvania School of Medicine, Philadephia, 19104, USA. · Clin Gastroenterol Hepatol. · Pubmed #15880315 No free full text.

Abstract: BACKGROUND & AIMS: Intestinal microbial flora participate in the pathogenesis of inflammatory bowel disease. Because antibiotic therapy alters intestinal microbial flora, we hypothesized that use of antibiotics might decrease the risk of flare. METHODS: We conducted a case-crossover study by using the General Practice Research Database from 1989-1997. Flares of disease were identified by receipt of a new prescription for either corticosteroids or mesalamine medications after an interval of at least 4 months without prescriptions for either class of medication. The primary exposure was receipt of any antibiotics in the 60 days preceding the index date. RESULTS: Among 1205 patients with Crohn's disease, exposure to antibiotics was associated with a reduced risk of flare (adjusted odds ratio [OR], 0.78; 95% confidence interval [CI], 0.64-0.96; P = .019). The effect was strongest with more recent exposure (test for trend, P < .05). Among 2230 patients with ulcerative colitis, use of any antibiotics within 60 days was not associated with flare of disease (adjusted OR, 0.96; 95% CI, 0.82-1.12; P = .581), although a potentially protective effect was observed in those patients with very recent exposure (exposure within 15 days: OR, 0.66; 95% CI, 0.51-0.85). CONCLUSIONS: Antibiotic use within 60 days was associated with a lower risk of flare of Crohn's disease, but not ulcerative colitis. The strength of the protective effect of antibiotics in Crohn's disease wanes over time.

Srinivasan R, Lewis JD. · Division of Gastroenterology, Presbyterian Medical Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Curr Opin Gastroenterol. · Pubmed #15703578 No free full text.

Abstract: The risk of luminal gastrointestinal tract, hepatobiliary tract, and non-gastrointestinal tract cancers in inflammatory bowel disease remains of great interest. The purpose of this review is to report on studies published in 2002 that have addressed several important questions related to the biology, natural history, and risk factors for colonic and extracolonic cancers. Two studies reported conflicting results on the natural history of low-grade dysplasia in patients with ulcerative colitis. Other investigators focused on the safety of medications used to treat inflammatory bowel disease, one noting no increased risk of cancer with azathioprine, another suggesting that anti-tumor necrosis factor therapy may increase the risk of lymphoma. Studies of patients after total proctocolectomy and ileoanal pouch anastomosis suggest that these patients continue to have a small risk of bowel cancer. A novel observation from studies focusing on the subgroup of patients with inflammatory bowel disease and primary sclerosing cholangitis was the identification of an increased risk of pancreatic cancer. Finally, many investigators continue to pursue potential biomarkers of malignancy for use in inflammatory bowel disease cancer surveillance programs. These studies have added to our knowledge of the risk of malignancy in inflammatory bowel disease and have set the stage for future long-term studies to better delineate the risk of lymphoma with the use of anti-tumor necrosis factor therapy and the fate of low-grade dysplasia in flat mucosa. Clinical application of potential biomarkers of malignancy in inflammatory bowel disease cancer surveillance is anticipated in the near future.

Lewis JD, Aberra FN, Lichtenstein GR, Bilker WB, Brensinger C, Strom BL. · Center for Clinical Epidemiology and Biostatistics and Department of Medicine, University of Pennsylvania Centers for Education and Research on Therapeutics, Philadelphia, 19104-6021, USA. · Gastroenterology. · Pubmed #14988820 No free full text.

Abstract: BACKGROUND & AIMS: Previous research has yielded conflicting data as to whether the natural history of inflammatory bowel disease follows a seasonal pattern. The purpose of this study was to determine whether relapse of inflammatory bowel disease follows a seasonal pattern either across a cohort of patients or within individual patients. METHODS: We used 1988 to 1997 data from the General Practice Research Database to conduct a retrospective cohort study of 1587 patients with Crohn's disease (mean age at start of follow-up, 41 +/- 17 years) and 2773 patients with ulcerative colitis (mean age at start of follow-up, 48 +/- 16 years). Flares of disease were identified by receipt of a new prescription for either corticosteroids or 5-ASA medications following an interval of at least 4 months without prescriptions for either class of medication. Logistic regression was used to adjust the association of season of the year and flare of disease for potential confounding variables. RESULTS: There was no association between season of the year and flare of Crohn's disease (P = 0.66). Season of the year was only weakly associated with flares of ulcerative colitis (P = 0.02). Compared with winter, spring had very slightly higher rates of flares (OR = 1.13, 95% CI: 1.05-1.23). We did not observe seasonal patterns within individual patients experiencing multiple flares (P > 0.05 for Crohn's disease and ulcerative colitis). CONCLUSIONS: Although we observed a slight increase in exacerbations of ulcerative colitis in the spring, in general, these data do not support an association between season of the year and flares.

Su C, Salzberg BA, Lewis JD, Deren JJ, Kornbluth A, Katzka DA, Stein RB, Adler DR, Lichtenstein GR. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. · Am J Gastroenterol. · Pubmed #12385442 No free full text.

Abstract: OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-alpha, infliximab, is effective in treating Crohn's disease. Preclinical studies suggest the importance of TNF-alpha in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication. METHODS: Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index. RESULTS: A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case. CONCLUSIONS: Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.

Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt F, Furth EE, Demissie EJ, Hurd LB, Su CG, Keilbaugh SA, Lazar MA, Wu GD. · Division of Gastroenterology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA. · Am J Gastroenterol. · Pubmed #11774944 No free full text.

Abstract: OBJECTIVES: Previous research has demonstrated that ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the gamma subtype of PPARs, as a therapy for active ulcerative colitis. METHODS: Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index. RESULTS: After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome. CONCLUSIONS: These data suggest that ligands for the gamma subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.

Higuchi LM, Joffe S, Neufeld EJ, Weisdorf S, Rosh J, Murch S, Devenyi A, Thompson JF, Lewis JD, Bousvaros A. · Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11740233 No free full text.

Abstract: OBJECTIVE: Previous reports suggest an association between inflammatory bowel disease (IBD) and immune thrombocytopenic purpura (ITP) in adults. To date, only five children with both diseases have been described. The aim of the study was to describe the characteristics of children with IBD and ITP. METHODS: Cases were obtained from the pediatric gastroenterology community by means of the pediatric gastroenterology internet bulletin board in June 1999. Eight cases were submitted from seven medical centers. Medical records were reviewed by two pediatric gastroenterologists and a pediatric hematologist. RESULTS: The age range of the patients was 2.1 to 16.5 years, with a mean age of 9.6 +/- 5.2 years. Four children had ulcerative colitis, three had Crohn disease, and one had indeterminate colitis. All had colonic involvement of IBD. Of eight patients, three had IBD first, three had ITP first, and two had both simultaneously. At ITP diagnosis, platelet count was less than 10,000/mL in five children, 17,000/mL in one child, and 50,000 to 60,000/mL in two children. Of the three children diagnosed with ITP first, two initially had rectal bleeding at the time of ITP diagnosis. Bone marrow evaluations, performed in six of eight children, were consistent with ITP. Six of the eight children had chronic ITP, including three children who were 5 years of age or younger. Therapy for ITP included steroids (n = 6), intravenous immunoglobulin (n = 6), Rh o (D) intravenous immunoglobulin (n = 2), and splenectomy (n = 1). CONCLUSIONS: The authors describe the largest pediatric case series of children with IBD and ITP. More than 50% of the children had the chronic form of ITP. Most patients responded to conventional therapy for ITP and IBD.

Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. · Gastroenterology. · Pubmed #11677199 No free full text.

Abstract: BACKGROUND & AIMS: Previous studies of the risk of lymphoma in inflammatory bowel disease patients have provided conflicting results. This study examines the risk of Hodgkin's and non-Hodgkin's lymphoma among patients with inflammatory bowel disease. METHODS: The authors performed a retrospective cohort study using the General Practice Research Database. Inflammatory bowel disease patients were matched to randomly selected controls on age, sex, and primary care practice. Lymphoma rates were also compared with published age- and sex-specific rates. RESULTS: The study included 6605 patients with Crohn's disease, 10,391 with ulcerative colitis, and 60,506 controls followed for an average of 3.7, 3.9, and 4.4 years, respectively. The incidence of lymphoma was not increased in patients with inflammatory bowel disease (relative risk = 1.20; 95% CI, 0.67-2.06). In subgroup analyses, an increased risk was not observed among patients with Crohn's disease (relative risk = 1.39; 95% CI, 0.50-3.40) or ulcerative colitis (relative risk = 1.11; 95% CI, 0.51-2.19). Compared with inflammatory bowel disease patients not treated with azathioprine or 6-MP, the relative risk of lymphoma among the 1465 inflammatory bowel disease patients treated with these medications (average, 106 mg/day for 2.0 years) was 1.27 (95% CI 0.03-8.20). CONCLUSIONS: Patients with inflammatory bowel disease do not have an increased risk of lymphoma as compared with the general population. Although we cannot completely rule out a modest increased risk of lymphoma with azathioprine or 6-MP therapy, an increased risk was not observed in this cohort.

Lewis JD. · No affiliation provided · Gastroenterology. · Pubmed #11487559 No free full text.

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