Systematic review: the costs of ulcerative colitis in Western countries.

BACKGROUND: Early onset and complications such as hospitalization and surgery contribute to the economic burden of ulcerative colitis. AIM: To review systematically the literature on costs of ulcerative colitis in Western countries. METHODS: Studies estimating costs of ulcerative colitis in Western countries were identified using Medline, EMBASE and ISI Web of Science and were rated based on relevance and reliability of estimates. All costs were adjusted to 2008 currency values. A parallel review focused on the impact of disease severity on costs, hospitalizations and surgeries. RESULTS: Estimated annual per-patient direct medical costs of ulcerative colitis ranged from $6217 to $11,477 in the United States and from euro8949 to euro10,395 in Europe. Hospitalizations accounted for 41-55% of direct medical costs. Indirect costs accounted for approximately one-third of total costs in the United States and 54-68% in Europe. Total economic burden of ulcerative colitis was estimated at $8.1-14.9 billion annually in the United States and at euro12.5-29.1 billion in Europe; total direct costs were $3.4-8.6 billion in the United States and euro5.4-12.6 billion in Europe. Direct costs, hospitalizations and surgeries increased with worsening disease severity. CONCLUSIONS: Ulcerative colitis is a costly disease. Hospitalizations contribute significantly to direct medical costs, and indirect costs are considerable, having previously been substantially underestimated.

Prevalence, number and morphological types of multinucleated histiocytic giant cells in equine inflammatory dermatoses: a retrospective light microscopic study of skin-biopsy specimens from 362 horses.

REASONS FOR PERFORMING STUDY: Multinucleated histiocytic giant cells (MHGC) are seen frequently in skin-biopsy specimens from horses with inflammatory dermatoses. However, the prevalence, number and morphological types of these cells have not been reported. OBJECTIVE: To determine the prevalence, number and morphological types of MHGC in equine inflammatory dermatoses, and the association of these cells with specific conditions. METHODS: Skin-biopsy specimens from 335 horses with inflammatory dermatoses and from 27 horses with normal skin were evaluated for the prevalence, number and morphological types of MHGC. RESULTS: The prevalence and number of MHGC were greater in granulomatous dermatoses than in nongranulomatous dermatoses. Infectious and noninfectious dermatoses were not different in terms of prevalence or morphological types of MHGC. Foreign-body MHGC were the predominant type in almost all cases. MHGC were not seen in normal skin. CONCLUSIONS: MHGC are seen in a wide variety of equine inflammatory dermatoses, especially those that are granulomatous. Number and morphological types of MHGC are of no apparent diagnostic significance. POTENTIAL RELEVANCE: MHGC are frequently present in a wide variety of inflammatory dermatoses in the horse. Because the prevalence, number and morphological types of MHGC are of minimal diagnostic significance, special stains and tissue cultures are necessary to confirm specific diagnoses.

Pulmonary actinomycosis complicating infliximab therapy for Crohn's disease.

The use of anti-tumour necrosis factor (TNF) agents has expanded significantly over the past few years, particularly for rheumatological diseases and Crohn's disease. A number of associated opportunistic infections have been observed as a result of suppression of T cell-mediated immunity, the most frequent being tuberculosis. We report the first case of pulmonary actinomycosis in a patient receiving regular infusions of infliximab, an anti-TNF agent, for Crohn's disease.

Review article: increasing the dose of oral mesalazine therapy for active ulcerative colitis does not improve remission rates.

BACKGROUND: Oral mesalazine (mesalamine, 5-aminosalicylic acid) formulations are effective in the treatment of active ulcerative colitis. All formulations contain the same active drug but differ with regard to mechanisms to deliver the drug to the colon. Patients who fail to respond to initial therapy are often administered higher doses of the same formulation. AIM: To review published trials of oral mesalazine formulations in treating active ulcerative colitis and to examine the effect of dose escalation on remission rates. RESULTS: Increasing the doses of oral mesalazine formulations does not result in higher remission rates, although increasing the doses of some formulations has been effective in increasing symptomatic improvement and/or response to treatment. CONCLUSIONS: Because oral mesalazine formulations do not demonstrate a significant dose response with regard to induction of remission of active ulcerative colitis, simple dose escalation may not be the most effective course for patients who fail to respond to initial mesalazine treatment.

Review article: evolutionary advances in the delivery of aminosalicylates for the treatment of ulcerative colitis.

Ulcerative colitis is a chronic and debilitating disease that involves inflammation of the colonic mucosa. Current therapies aim to reduce the symptom burden of ulcerative colitis and maintain disease quiescence. The standard first-line treatment for mild-to-moderate ulcerative colitis is 5-aminosalicylate therapy, which is available in oral and rectal (topical) formulations. While current 5-aminosalicylate formulations are effective in the majority of patients, they are associated with a number of limitations including inconvenient dosing regimens and poor patient acceptability, which may lead to non-compliance with prescribed therapy. A variety of improved delivery mechanisms have been developed in an effort to overcome these limitations. Micropellet formulations and high-dose tablets appear to offer comparable efficacy and tolerability to conventional formulations, although any benefit in terms of long-term patient compliance remains to be proven. Novel methods of delivery, such as those using a combination of hydrophilic and lipophilic matrices, designed to provide once-daily dosing in a high-strength tablet, may offer a significant improvement in the therapy of active and quiescent ulcerative colitis. This review examines the limitations of current 5-aminosalicylate formulations and reports on the evolution of novel oral formulations designed to overcome these limitations, maximize patient compliance during both induction and maintenance of quiescence, and optimize overall clinical outcomes.

Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease.

AIM: To study the effects of infliximab on pregnancy and foetal outcome. METHODS: We conducted a retrospective chart review of women with Crohn's disease treated intentionally with infliximab during pregnancy. The primary outcome measure was the occurrence of congenital malformations. Secondary outcome measures were the rate of premature birth, low-birth weight, small for gestational age infants, intrauterine growth retardation and caesarean section. RESULTS: Ten women were identified. Eight women received maintenance infliximab infusions throughout their pregnancy and two women received their initial infliximab infusions during pregnancy. All 10 pregnancies ended in live births. No infants had congenital malformations, intrauterine growth retardation or small for gestational age parameters. Three infants were premature and one had low-birth weight. Eight women had a caesarean section. CONCLUSIONS: This is the first reported series of intentional infliximab use throughout pregnancy. These data, combined with other studies of inadvertent use of infliximab during pregnancy, suggest that the benefits of infliximab in achieving response and maintaining remission in mothers with Crohn's disease may outweigh the risk to the foetus of exposure to the drug. Further prospective data collection will be helpful to confirm these findings.

The quality of life in patients with Crohn's disease.

BACKGROUND: Health-related quality of life studies provide insight into the influence of Crohn's disease on patients' lives, and the potential impact on professional and personal productivity. AIM: To compare health-related quality of life in Crohn's disease patients with that in other patients and healthy controls, and between medically and surgically treated Crohn's disease patients, and to correlate health-related quality of life with Crohn's disease activity. METHODS: An expanded MEDLINE search of full length, English language, adult Crohn's disease studies from January 1966 to September 2000 was performed. The key words utilized were: 'Quality of Life', 'Health Status' or 'Health Related Quality of Life' and 'Crohn's' or 'Inflammatory Bowel Disease'. RESULTS: A total of 258 articles were identified; 236 subsequently were excluded, leaving 22 for analysis. Compared with Crohn's disease patients, the health-related quality of life was better in healthy controls and in ulcerative colitis patients (except pre-colectomy), but similar to or worse than that in many other medical conditions. The health-related quality of life was directly correlated with Crohn's disease activity, and was worse in active disease than in remission. The health-related quality of life was improved only in the short term in surgically vs. medically treated Crohn's disease patients. CONCLUSIONS: Health-related quality of life analysis provides important insights into the impact of Crohn's disease, and should be included in clinical trials. Researchers, clinicians and other health care providers need to be cognizant of the impact of the health-related quality of life upon patients' lives.

Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis.

OBJECTIVE: There are scant data regarding outpatient adherence in quiescent ulcerative colitis aside from patients enrolled in controlled clinical trials. We conducted a prevalence study to determine the medication adherence rate of maintenance therapy and to identify possible risk factors for nonadherence. METHODS: Outpatients with clinically quiescent ulcerative colitis for >6 months on maintenance mesalamine (Asacol, Procter and Gamble, Cincinnati, OH) were eligible. Patients were interviewed regarding disease history, and demographics were obtained from medical records. Refill information for at least 6 months was obtained from computerized pharmacy records. Adherence was defined as at least 80% consumption of supply dispensed. Using nonadherence as the outcome of interest, stratified analysis and regression modeling were used to identify significant associations. RESULTS: Data were complete for the 94 patients recruited. The overall adherence rate was found to be 40%. The median amount of medication dispensed per patient was 71% (8-130%) of the prescribed regimen. Nonadherent patients were more likely to be male (67% vs 52%, p < 0.05), single (68% vs 53%, p = 0.04), and to have disease limited to the left side of the colon versus pancolitis (83% vs 51%, p < 0.01). Sixty-eight percent of patients who took more than four prescription medications were found to be nonadherent versus only 40% of those patients taking fewer medications (p = 0.05). Age, occupation, a family history of inflammatory bowel disease, length of remission, quality-of-life score, or method of recruitment (telephone interview vs clinical visit) were not associated with nonadherence. Logistic regression identified that a history of more than four prescriptions (odds ratio [OR] 2.5 [1.4-5.7]) and male gender (OR 2.06 [1.17-4.88]) increased the risk of nonadherence. Two statistically significant variables, which were protective against nonadherence, were endoscopy within the past 24 months (OR 0.96 [0.93-0.99]) and being married (OR 0.46 [0.39-0.57]). CONCLUSION: Nonadherence is associated with multiple concomitant medications, male gender, and single status. These patient characteristics may be helpful in targeting those patients at higher risk for nonadherence.

Evolving medical therapies for ulcerative colitis.

Patients with ulcerative colitis have traditionally relied on sulfasalazine, mesalamine, and corticosteroids as the mainstay of medical therapy. Steroid-refractory, -dependent, or -intolerant patients have resorted to agents such as cyclosporine for short-term efficacy and 6-mercaptopurine or azathioprine for long-term efficacy. The next generation of evolving therapies includes many novel agents that target various aspects of the human immune response. Therapies that block the production or action of tumor necrosis factor have received much interest in inflammatory bowel disease. Treatments currently under study include interleukins, interferons, T-cell selective antibodies, molecules involved in cellular trafficking and signaling, mucosal healing or growth factors, and novel steroid agents. Other "less traditional" therapies, including probiotics, heparins, and anti-gastric ulcer remedies, challenge our understanding of the pathogenesis of ulcerative colitis and may provide further insights into future therapies.

Lactate supply as a determinant of the distribution of intracellular pH within the hepatic lobule.

When isolated livers from starved rats are perfused with lactate at constant perfusate pH and P(co(2)), there is a marked gradient of cell pH (pH(i)) along the length of the lobular radius, with periportal cells being substantially more alkaline than perivenous cells. In the present studies, the perivenous 21% of the lobular volume was destroyed by retrograde digitonin perfusion, and antegrade perfusion restored. pH(i) was determined by (31)P-NMR. The remaining periportal cells, the site of gluconeogenesis from lactate, had a substantially higher mean pH(i) (7.42) than did the intact liver (7.23). When lactate was removed from the perfusate, mean pH(i) decreased to 7.25. The corresponding concentration of cell bicarbonate fell with a half-time of approximately 5 min. When lactate was re-introduced mean pH(i) rose to 7.34. We conclude that a major contributor to periportal alkalinity under these conditions is proton consumption during gluconeogenesis from lactate ions.

Efficacy and safety of repeated infliximab infusions for Crohn's disease: 1-year clinical experience.

Data from clinical trials suggest the efficacy of the chimeric tumor necrosis factor alpha monoclonal antibody infliximab in improving clinical, endoscopic, and histologic outcomes in patients with moderately to severely active Crohn's disease (CD) and fistulizing CD. To determine whether the efficacy and safety record of infliximab reported in clinical trials would be reflected in clinical use, clinical experience with infliximab was assessed in patients with CD at the University of Chicago, Chicago, Illinois. All patients with CD at this institution receiving infliximab in the first year of its release were prospectively followed up for 1 year. Disease activity was scored at the time of the initial infusion and at 1, 3, 7, and 12 weeks after infusion. Results were analyzed separately for patients with luminal or fistulous CD. Clinical response, remission, corticosteroid tapering, and adverse event data were collected. A total of 129 patients with luminal (n = 81) or fistulous (n = 48) disease received a mean of 2.38 and 3.23 infusions of infliximab per patient, respectively. After the initial infusion course, clinical response and remission rates at 3 weeks were 65% and 31% for patients with luminal disease and 78% and 24% for patients with fistulous disease, respectively. Clinical response and remission after the first infusion occurred at a median of 8 days and 9 days, respectively. In those patients who subsequently relapsed, relapses occurred after a mean of 8.5 weeks and 12.2 weeks in patients with luminal and fistulizing disease, respectively. Corticosteroid tapering was possible in > 90% of patients (luminal disease) after the initial infusion and complete withdrawal in 54% after the second infusion, with a sustained median steroid dose of 0 mg from the 4-month time-point onward. Infusion reactions or adverse events occurred in 5-13% of patients during or immediately after the initial infusion of infliximab; most were mild and easily managed and did not increase in incidence with subsequent infusions. Clinical experience with infliximab closely mirrors the findings of controlled clinical trials. Repeated administration of infliximab was efficacious and relatively well tolerated in patients with CD and demonstrated corticosteroid-sparing benefits.

Religious attendance increases survival by improving and maintaining good health behaviors, mental health, and social relationships.

Several recent prospective analyses involving community-based populations have demonstrated a protective effect on survival for frequent attendance at religious services. How such involvement increases survival are unclear. To test the hypothesis that religious attendance might serve to improve and maintain good health behaviors, mental health, and social relationships, changes and consistencies in these variables were studied between 1965 and 1994 for 2,676 Alameda County Study participants, from 17 to 65 years of age in 1965, who survived to 1994. Measures included smoking, physical activity, alcohol consumption, medical checkups, depression, social interactions, and marital status. Those reporting weekly religious attendance in 1965 were more likely to both improve poor health behaviors and maintain good ones by 1994 than were those whose attendance was less or none. Weekly attendance was also associated with improving and maintaining good mental health, increased social relationships, and marital stability. Results were stronger for women in improving poor health behaviors and mental health, consistent with known gender differences in associations between religious attendance and survival. Further understanding the mechanisms involved could aid health promotion and intervention efforts.

Efficacy of parenteral methotrexate in refractory Crohn's disease.

BACKGROUND: Methotrexate is steroid-sparing in short-term trials for refractory Crohn's disease. This study assesses the impact of dosing and administration on the long-term utility of methotrexate in Crohn's disease. METHODS: The efficacy and tolerability of methotrexate were assessed in all refractory Crohn's disease patients treated at the University of Chicago from 1 September 1989 to 6 June 1997. RESULTS: Seventy-six patients were identified: 43% male, mean age 35 years, mean Crohn's disease duration 9.5 years. Mean methotrexate duration was 55 weeks; mean dose was 20 mg/week. Drug administration was parenteral (78%), oral (13%), or combination (8%). Improvement occurred in 63% after a mean of 9 weeks, for a mean duration of 65 weeks. Remission occurred in 37% after a mean of 22 weeks, for a mean duration of 59 weeks. Improvement and remission were highest with parenteral therapy, but dose-independent. Parenteral therapy maintained remission in 46%. Improvement (P=0.05) and remission (P=0.01) were more likely for patients under 40. Improvement rates were higher with concurrent steroids (P=0.02) or antibiotics (P=0.01). Side-effects occurred in 46%, resulting in discontinuation in 18%. Prednisone was decreased in 78%, and stopped in 40%. CONCLUSIONS: Long-term therapy with methotrexate in Crohn's disease is safe, effective, steroid-sparing, and most efficacious in younger patients and when given parenterally.

Standing at work and progression of carotid atherosclerosis.

OBJECTIVES: The association between the amount of standing at work and the progression of carotid intima media thickness (IMT) was studied among 584 active working men participating in the Kuopio Ischemic Heart Disease Risk Factor Study. METHODS: Ultrasound measurements of atherosclerotic changes in the carotid arteries were performed at the beginning of the study and after 4 years. Analyses of changes in IMT included adjustments for risk factors and stratification by base-line levels of atherosclerosis and prevalent ischemic heart disease (IHD). RESULTS: Significant relationships were found between the amount of standing at work and atherosclerotic progression. After adjustment for the heaviness of the work, psychosocial job factors, income, and biological and behavioral risk factors, the mean change in maximum IMT for those standing not at all, a little, a lot, and very much was 0.24, 0.25, 0.28, and 0.33 mm, respectively. For men with IHD the respective changes were 0.08, 0.15, 0.37, and 0.75 mm -- a 9-fold difference between the no-exposure and high-exposure group. For the men with carotid stenosis, the respective difference was 3-fold. CONCLUSIONS: These findings provide the first empirical support in a population study for the role of hemodynamic factors in the progression of atherosclerosis induced by long-term standing. Men with carotid stenosis or IHD appear especially vulnerable to the adverse effects associated with standing at work. Reducing the duration of standing at work should be considered both in the occupational rehabilitation of such patients and in the primary prevention of atherosclerosis.

Hepatic intralobular mapping of fructose metabolism in the rat liver.

Detailed mapping of glucose and lactate metabolism along the radius of the hepatic lobule was performed in situ in rat livers perfused with 1.5 mM lactate before and during the addition of 5 mM fructose. The majority of fructose uptake occurred in the periportal region; 45% of fructose taken up in the periportal half of the lobular volume being converted into glucose. Periportal lactate uptake was markedly decreased by addition of fructose. Basal perivenous lactate output, which was derived from glucose synthesized periportally, was increased in the presence of fructose. During fructose infusion there was a small decrease in cell pH periportally, but acidification of up to 0.5 pH units perivenously. The evidence suggests that in situ the apparent direct conversion of fructose into lactate represents, to a substantial extent, the result of periportal conversion of fructose into glucose and the subsequent uptake and glycolysis to lactate in the perivenous zone of some of that glucose. (31)P NMR spectroscopy showed that the cellular concentration of phosphomonoesters changes very little periportally during fructose infusion, but there was an approximate twofold increase perivenously, presumably due to the accumulation of fructose 1-phosphate. It may be inferred that fructokinase activity is expressed throughout the hepatic lobule.