Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study.

Crohn's disease (CD) is associated with a higher type-1-helper T cell (Th1) cytokine expression, whereas ulcerative colitis (UC) appears to express a modified Th2 response. In addition to its classic role in calcium homeostasis, calcitriol, the hormonal active form of vitamin D, exerts immunoregulatory effects such as modulation of Th1/Th2 cytokines. Therefore, calcitriol administration could modify immune dysfunction in CD and UC. Nine patients with UC (M/F: 5/4; mean age 47 years, remission(R)/active(A) disease: 7/2), 8 patients with CD (M/F: 2/6; mean age 36, R/A 5/3) and 6 healthy controls (HC) (M/F: 3/3, mean age 4) were enrolled. Peripheral blood was collected after a drug-washout of 15 days and peripheral blood mononuclear cells were stimulated with mitogens alone or in the presence of physiological concentrations of calcitriol (100 pg/ml). Type 1 (IL-2, TNF-alpha, IFN-gamma) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-alpha production was significantly higher both in UC (p=0.0002) and CD (p=0.0001) patients, at baseline and after incubation with calcitriol (UC p=0.0003, CD p=0.0009). The effects of calcitriol incubation were: 1) reduced IFN-gamma (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-alpha production in CD (p=0.032); 3) no significant effects in HC. Calcitriol increased, albeit not significantly, IL-10 production in UC compared to CD patients (p=0.09). These results suggest an important modulatory role of vitamin D in the Th1/Th2 immune response. The observation that the effect of this modulation was different in CD compared to UC patients provides an interesting area of research into the pathogenesis and treatment of these inflammatory conditions.

Assessment of gastro-oesophageal reflux symptoms in Italian physicians -- a survey by Reflux Disease Questionnaire.

BACKGROUND: The prevalence of gastro-oesophageal reflux disease symptoms in physicians, as compared to that of the general population, is not known. METHODS: We submitted a validated Italian version of a simple questionnaire (Reflux Disease Questionnaire) to 490 physicians and 430 controls to assess: (i) the presence, frequency and severity of gastro-oesophageal reflux disease symptoms in the two populations; (ii) how the self-assessment of troublesome gastro-oesophageal reflux disease symptoms by physicians correlate with a pathological Reflux Disease Questionnaire, judged on the basis of a total Reflux Disease Questionnaire score >or=8. RESULTS: A valid and complete questionnaire was obtained in 456/490 (93.1%) physicians and 367/430 (85.3%) controls. Between the two groups there were no differences in terms of total Reflux Disease Questionnaire score or individual items, with the only exception of "severity of burning feeling behind breastbone" which was significantly higher in the physician group. An excellent correlation was found between the self-assessment by physician and the total Reflux Disease Questionnaire score. CONCLUSIONS: The prevalence of gastro-oesophageal reflux disease symptoms among Italian doctors is not different from that reported by a matched control group, and that their ability in self-assessing a troublesome gastro-oesophageal reflux disease is optimal.

Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease.

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

Review article: the management of steroid dependency in ulcerative colitis.

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

The lessons learned from randomized clinical trials of GERD.

Despite the huge number of randomized controlled clinical trials published on gastro-oesophageal reflux disease, the translation of the information gathered into clinical practice is rather limited. The aim of this article is to summarize the results of pivotal randomized controlled clinical trials and review articles on reflux disease and evaluate to what extent their results can be applied to current clinical practice. We reviewed the most relevant randomized controlled clinical trials and reviews since the publication of the first randomized controlled clinical trial on reflux oesophagitis (1978) to date. Six areas were explored, namely: (1) diagnostic "entry" criteria, (2) efficacy parameters, (3) duration of therapy, (4) degree of antisecretory effect, (5) placebo effect, (6) follow-up data. Gastro-oesophageal reflux disease is now the most frequent upper GI disorder treated by gastroenterologists in Europe and North America. There is still a dearth of information regarding the natural history of the disease. The types of information generated through randomized controlled clinical trials have had only limited applicability to routine clinical practice. In the future, large cooperative databases accumulating the clinical histories of a great variety of gastro-oesophageal reflux disease patients may help to provide us with the much needed insights into the natural history of this common disorder.

COXIBs and non-selective NSAIDs in the gastroenterological setting: what should patients and physicians do?

Although adverse effects of nonsteroidal anti-inflammatory drugs occur in only a small proportion of users, the widespread use of these drugs has resulted in a substantial overall number of affected persons who experience serious gastrointestinal complications. Dyspeptic symptoms are estimated to occur in 10-60% of nonsteroidal anti-inflammatory drug users and lead to discontinuation of treatment in 5-15% of rheumatoid arthritis patients taking nonsteroidal anti-inflammatory drugs. It is now well established that the point prevalence of peptic ulcer disease in patients receiving conventional nonsteroidal anti-inflammatory drug therapy ranges between 10 and 30%, representing a 10- to 30-fold increase over that found in the general population. One out of 175 users of conventional nonsteroidal anti-inflammatory drugs in the USA will be hospitalized each year for nonsteroidal anti-inflammatory drug-induced gastrointestinal damage. The mortality of hospitalized patients remains about 5-10%, with an expected annual death rate of 0.08%. The selective COX-2 inhibitors consistently show comparable efficacy to that of conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis and osteoarthritis, but have a reduced propensity to cause gastrointestinal toxicity. In many cases, the gastric effects of therapeutically active doses of COX-2 inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to those of combined therapy with conventional nonsteroidal anti-inflammatory drugs and gastroprotective agents. These findings warrant the consideration of COX-2 inhibitors as first-line therapy in patients requiring long-term pain control.

Is interferon-alpha therapy safe and effective for patients with chronic hepatitis C and inflammatory bowel disease? A case-control study.

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

Autoantibody profile during short-term infliximab treatment for Crohn's disease: a prospective cohort study.

BACKGROUND: The potential clinical implications of autoimmunity during treatment with infliximab are unclear. AIM: To determine the frequency and correlation of autoantibody formation in patients with Crohn's disease treated with infliximab in a routine clinical setting. METHODS: Sixty-three patients with refractory/inflammatory (31) and/or fistulising Crohn's disease (32), received an infliximab infusion at a dose 5 mg/kg in weeks 0, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated. RESULTS: Antinuclear antibodies were found in five of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, nine of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and two more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage. CONCLUSIONS: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with Crohn's disease receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.

Rabeprazole is equivalent to omeprazole in the treatment of erosive gastro-oesophageal reflux disease. A randomised, double-blind, comparative study of rabeprazole and omeprazole 20 mg in acute treatment of reflux oesophagitis, followed by a maintenance open-label, low-dose therapy with rabeprazole.

BACKGROUND: Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones. AIM: To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis. METHODS: Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks. RESULTS: After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p<0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse. CONCLUSION: Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.

Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection.

OBJECTIVE: To determine the prevalence of cytomegalovirus infection in patients with steroid-refractory ulcerative colitis who required colonic resection, and to assess its possible association with the use of immunosuppressive and steroid treatment and outcome after colectomy. PATIENTS AND METHODS: The study included surgical specimens and related pre-operative endoscopic biopsy specimens of 77 consecutive ulcerative colitis patients (34 females) who underwent colectomy because of intractable steroid-refractory ulcerative colitis (55 patients), toxic megacolon (6 patients), dysplasia or cancer (7 patients) or loss of function of the colon (9 patients). Clinical features and current and past treatments were analysed. Haematoxylin and eosin and specific immunohistochemical staining for cytomegalovirus were used to detect inclusion bodies in all specimens. RESULTS: Cytomegalovirus infection was found in 15 of 55 steroid-refractory ulcerative colitis patients (27.3%) and in 2 of 22 non-refractory patients (9.1%) (p=0.123). Only six patients had positive staining for cytomegalovirus in pre-operative endoscopic biopsy specimens. Detection of cytomegalovirus inclusion in biopsy specimens was not related to the number of biopsies or to time that had elapsed since colonoscopy and index surgery. Cytomegalovirus-positive patients were more likely to be on systemic corticosteroids (p=0.03). In contrast, current use and duration of immunosuppressive treatment, number of steroid cycles since diagnosis and in the last year, as well as chronic use of steroid in the last year were not significantly related to cytomegalovirus infection. Cytomegalovirus-positive patients did not receive antiviral therapy following proctocolectomy but did not show endoscopic or histological cytomegalovirus reactivation in the ileo-anal pouch and in the remaining bowel. CONCLUSIONS: Cytomegalovirus infection is frequently found in surgical specimens of patients with steroid-refractory ulcerative colitis and is more likely in patients on corticosteroid treatment. Cytomegalovirus infection is frequently unrecognised in pre-operative biopsy specimens, thus raising concerns about the accuracy of the available diagnostic tools. Unrecognised and untreated cytomegalovirus infection does not affect the outcome of ulcerative colitis patients following proctocolectomy.

Role or carbon dioxide-releasing suppositories in the treatment of chronic functional constipation: a double-blind, randomised, placebo-controlled trial.

OBJECTIVE: Treatment of chronic functional constipation is difficult. Both oral and topical laxatives may fail to adequately relieve symptoms, and there is risk of adverse effects such as functional or structural changes in the intestine, together with electrolyte disturbances. The aim of this study was to evaluate the efficacy and safety of a suppository that combines sodium bicarbonate and potassium bitartrate in a polyethylene glycol base to generate approximately 175mL of carbon dioxide (CO(2)). This release distends the rectal ampulla, thereby stimulating peristalsis and a subsequent bowel movement. PATIENTS AND METHODS: This was a prospective, crossover, double-blind, randomised, placebo-controlled, sequential study of outpatients with chronic functional constipation. Each patient received two suppositories of identical appearance, containing active drug or placebo. The sequence of active drug-placebo (sequence 1) or placebo-active drug (sequence 2) was randomised in groups of eight. The second suppository was taken 7 days after the first. The following parameters were evaluated and scored: evacuation time, type of evacuation, feeling of emptying of the rectal ampulla, stool characteristics, anal complaints, abdominal pain and overall patient assessment. RESULTS: A total of 29 patients entered the study. According to a restricted sequential plan, a statistical significance (p < 0.05) in favour of the active drug was reached after 26 patients. A positive response within 30 minutes of introduction of the suppository occurred in 51.7% and 6.9% of patients treated with the active drug and placebo, respectively (p = 0.0003). Normal evacuation occurred in 65.5% and 24.1% of patients treated with the active drug and placebo, respectively (p = 0.004). Normal stool consistency was found in 44.8% and 7.2% of patients treated with the active drug and placebo, respectively (p = 0.04). Patient assessment of treatment as satisfactory occurred in 51.7% and 20.7% of subjects treated with the active drug and placebo, respectively (p = 0.029). Only a trend in favour of the active drug was observed with regard to feeling of incomplete evacuation, and active drug was comparable to placebo with regard to anal and abdominal tolerability CONCLUSION: The CO(2)-releasing suppository may represent an alternative to rectal laxatives for the relief of chronic functional constipation. The data obtained in this study indicate that CO(2)-releasing suppositories may be usefully and safely employed in the treatment of patients at risk for electrolyte disorders such as the elderly or patients with renal or cardiovascular disorders.

Can nausea and vomiting be treated with ginger extract?

Ginger (Zingiber officinale) is a spice traditionally used to treat indigestion, nausea and vomiting. Ginger extracts accelerate gastric emptying and stimulate gastric antral contractions. These effects are mainly due to the presence of gingerols and shogaols and their activity on cholinergic M receptors and serotonergic 5-HT and 5-HT receptors. Various researches on this subject have led to controversial results, due to the chemical instability of ginger extracts and particularly of gingerols, which are readily-oxidizable substances. A systematic review of double-blind, placebo-controlled, randomized studies highlighted the potential efficacy of ginger on the prevention and treatment of nausea and vomiting of various origins, even though additional controlled studies are needed. This review focuses on pregnancy-induced nausea and vomiting and on chemotherapy induced nausea, and hypothesizes a therapeutic role for ginger extracts in case of side effects, as an alternative to traditional prokinetic drugs such as domperidone, levosulpiride or metoclopramide.

Nonsteroidal anti-inflammatory drug gastropathy and Helicobacter pylori: the search for an improbable consensus.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are known to share a number of pathogenic mechanisms, but there is no evidence to show a significant synergistic action between these two risk factors. Studies to assess possible interactions in the pathogenesis of dyspepsia and upper gastrointestinal mucosal lesions have differed in their endpoints, the definition of dyspepsia, and the regimens used for eradication of H. pylori. However, some conclusions may be drawn from the results of clinical trials. As far as dyspepsia is concerned, an association between NSAID dyspepsia and infection with H. pylori, seems likely, but it is difficult to make sense of the discrepant data that are currently available. On the contrary, neither short- nor long-term NSAID administration presents a definite major risk of gastric and duodenal injury or, above all, of ulcer-related complications (bleeding or perforation) in H. pylori-positive patients. Based on these considerations, what recommendations can be made with regard to H. pylori eradication in patients requiring treatment with NSAIDs? H. pylori and anti-inflammatory drugs are probably independent causes of gastric and duodenal damage. Patients taking NSAIDs who are found to have gastric or duodenal ulcers should, therefore, be tested for the bacterium and specifically treated, because H. pylori and NSAID-induced ulcers may be macroscopically indistinguishable. Whether asymptomatic patients taking NSAIDs should be tested and treated for H. pylori infection is still a matter of debate.

A practical guide to the management of distal ulcerative colitis.

This article reviews the role of corticosteroids, sulfasalazine and mesalazine (5-aminosalicylic acid, mesalamine), immunosuppressive agents and alternative novel drugs for the treatment of distal ulcerative colitis. Short cycles of traditional, rectally administered corticosteroids (methylprednisolone, betamethasone, hydrocortisone) are effective for the treatment of mild to moderately active distal ulcerative colitis. In this context, their systemic administration is limited to patients who are refractory to either oral 5-amino-salicylates, topical mesalazine or topical corticosteroids. Of no value in maintaining remission, the long term use of either or topical corticosteroids may be hazardous. A new class of topically acting corticosteroids [budesonide, fluticasone, beclomethasone dipropionate, prednisolone-21-methasulphobenzoate, tixocortol (tixocortol pivalate)] represents a valid alternative for the treatment of active ulcerative colitis, and may be useful in the treatment of refractory distal ulcerative colitis. Although there is controversy concerning dosage or duration of therapy, oral and topical mesalazine is effective in the treatment of mild to moderately active distal ulcerative colitis. Sulfasalazine and mesalazine remain the first-choice drugs for the maintenance therapy of distal ulcerative colitis. Evidence exists showing a trend to a higher remission rate with higher doses of oral mesalazine. Topical mesalazine (suppositories or enemas) also is effective in maintenance treatment. For patients with chronically active or corticosteroid-dependent disease, azathioprine and mercaptopurine are effective in reducing either the need for corticosteroids or clinical relapses. Moreover, they are effective for long term maintenance remission. Cyclosporin may be useful in inducing remission in patients with acutely severe disease who do not achieve remission with an intensive intravenous regimen. Existing data suggest that azathioprine and mercaptopurine may be effective in prolonging remission in these patients. The role of alternative drugs for the treatment of distal ulcerative colitis and its different forms is reviewed. In particular data are reported concerning the effectiveness of 5-lipoxygenase inhibitors, topical use of short chain fatty acids, nicotine, local anaesthetics, bismuth subsalicylate enema, sucralfate, clonidine, free radical scavengers, heparin and hydroxychloroquine.

Long term treatment of duodenal ulcer. A review of management options.

Duodenal ulcer is a chronic disease characterised by remission and relapses. The duration of this relapsing tendency is unpredictable for the individual patient, but in most cases it lasts for many years and perhaps the entire lifetime. Various therapeutic strategies have been suggested to maintain the disease in remission: continuous, intermittent and on-demand treatment with H2-antagonists, or surgery. Continuous maintenance treatment with the currently available H2-blockers has proved to be superior to all the other strategies in terms of efficacy, and should therefore be regarded as the long term treatment of choice for duodenal ulcer patients. The duration of maintenance treatment is still uncertain, but probably it should not be less than a few years. Intermittent treatment or surgery could be proposed to patients unsuitable for continuous maintenance, depending on whether they have mild or aggressive disease, respectively.

Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations.

Although adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) occur in only a small proportion of users, the widespread use of these drugs has resulted in a substantial overall number of affected persons who experience serious gastrointestinal complications. Dyspeptic symptoms are estimated to occur in 10-60% of NSAID users and lead to discontinuation of treatment in 5-15% of rheumatoid arthritis patients taking NSAIDs. It is now well established that the point prevalence of peptic ulcer disease in patients receiving conventional NSAID therapy ranges between 10 and 30%, representing a 10-30-fold increase over that found in the general population. One of 175 users of conventional NSAIDs in the USA will be hospitalized each year for NSAID-induced gastrointestinal damage. The mortality of hospitalized patients remains about 5-10%, with an expected annual death rate of 0.08%. The selective COX-II inhibitors (rofecoxib, celecoxib, parecoxib, etoricoxib, valdecoxib, lumiracoxib) show consistently comparable efficacy to that of conventional non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis and osteoarthritis, but have a significantly reduced propensity to cause gastrointestinal toxicity. In many cases, the gastric effects of therapeutically active doses of COX-II inhibitors are indistinguishable from placebo. The safety benefits of COX-2 inhibitors given alone appear similar to combined therapy with conventional NSAIDs and gastroprotective agents. These findings warrant the consideration of COX-II inhibitors as first-line therapy in patients requiring long-term pain control.

Review article: Helicobacter pylori and NSAID gastropathy.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are known to share a number of pathogenic mechanisms, but there is no evidence to show a significant synergic action between the two risk factors. Studies assessing this subject have differed in almost every aspect of their methodology, including the definition of a NSAID user as well as the types, doses, duration and their indications for NSAID use. They also differed in their end-points, the definition of dyspepsia and the regimes used for eradication of H. pylori. However, some conclusions may be drawn from the results of clinical trials. In H. pylori-positive patients without mucosal lesions, NSAIDs may aggravate dyspeptic symptoms but, with the exception of elderly patients, they do not present a definite major risk of gastric and duodenal lesions and, above all, of ulcer-correlated complications. So what recommendations can be made with regard to H. pylori eradication in patients requiring treatment with NSAIDs? The microorganism and the anti-inflammatory drugs are undoubtedly independent causes of gastric and duodenal damage. Patients taking NSAIDs who are found to have gastric or duodenal ulcers should therefore be tested for the bacterium and specifically treated, since H. pylori and NSAID-induced ulcers may be macroscopically indistinguishable. Whether asymptomatic patients taking NSAIDs should be tested and treated for H. pylori infection is still a matter of debate.

Double-blind, randomized trial of roxatidine 150 mg in the early evening versus bedtime administration in the short-term treatment of duodenal ulcer.

AIM: To compare the efficacy and tolerability of early evening (19.00-21.00 hours) vs. bedtime (22.00-00.00 hours) oral administration of roxatidine 150 mg in the short-term treatment of active duodenal ulcer. METHODS: The trial was randomized, double-blind and double-dummy, with parallel groups. A total of 276 patients were recruited and randomly assigned either to roxatidine in the early evening (n = 139) or roxatidine at bedtime (n = 137). RESULTS: After 4 weeks, 78% of patients receiving roxatidine in the early evening and 74% of those treated at bedtime had achieved complete healing, as determined by per-protocol analysis. With intention-to-treat analysis the healing rates were 70.5% and 70.8%, respectively. After 8 weeks the healing rates in the early evening and bedtime treatment groups were 92% and 95% (per-protocol analysis) and 78% and 84% (intention-to-treat analysis). Both treatments proved effective in reducing the frequency and severity of daytime and nocturnal epigastric pain, as well as other ulcer-related symptoms. CONCLUSIONS: This study confirmed the healing and analgesic properties of roxatidine in duodenal ulcer disease. Early evening or bedtime dosing with roxatidine 150 mg resulted in similar 4- to 8-week rates of duodenal ulcer healing.

Prospective audit of gastroscopy under the 'three-day rule': a regional initiative in Italy to reduce waiting time for suspected malignancy.

BACKGROUND: A regional initiative, called the 'three-day rule', has recently been introduced in Italy to facilitate the earlier diagnosis of malignancy. It requires patients with suspected severe diseases to have a diagnostic procedure performed within three working days of referral by a general practitioner. AIM: To assess prospectively the effectiveness and compliance with the three-day rule for upper digestive malignancies. METHODS: We compared patients referred for gastroscopy under the three-day rule initiative with contemporaneous open access referrals over a 12-month period at a single large teaching hospital in west Milan. We compared the prevalence of malignancies and other serious non-neoplastic diseases as well as the waiting times in the two groups. The appropriateness of the indications for each referral was also reviewed by a gastroenterologist blind to the outcome of the test. RESULTS: One hundred and forty-two patients referred for gastroscopy under the three-day rule scheme and 767 routine referrals were studied. Significantly more oesophageal/gastric cancers (6% vs. 1%) and serious benign gastrointestinal lesions (grade II-III oesophagitis or peptic ulcer) were diagnosed in three-day rule patients in comparison with routine referrals (P < 0.05). The rate of inappropriate referral was significantly lower in the three-day rule group than in the open access group (39% vs. 22%) (P < 0.01). The estimated cost of the three-day rule scheme (in extra list examinations alone) was 10 780 euros, with about 1198 euros per diagnosis of cancer, but only 229.5 euros per 'useful' diagnosis (including peptic ulcer disease and oesophagitis). CONCLUSIONS: Significantly more upper gastrointestinal cancers and serious benign diseases can be found within a short period to comply with the three-day rule scheme. However, some general practitioners appear to over-interpret alarm symptoms, leading to some inappropriate referrals. Better awareness of appropriate urgent referral criteria is needed in order to ensure that the best use is made of the resources available.

Why are non-steroidal anti-inflammatory drugs important in peptic ulceration?

The pathogenetic role of non-steroidal anti-inflammatory drugs (NSAIDs) in peptic ulcer disease is reviewed, on the basis of available experimental and epidemiological knowledge. In addition, original clinical data are provided concerning the prophylactic and therapeutic role of the H2-receptor antagonists ranitidine and cimetidine, and colloidal bismuth subcitrate, in the treatment of NSAID-associated peptic lesions in rheumatic patients.