G. Manzionna

Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study

BACKGROUND AND AIMS The efficacy of azathioprine in the treatment of chronic active Crohns disease is well established. However, this drug has a long onset of action. Methotrexate has also been shown to be effective in chronic active Crohns disease. The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine, and to establish whether methotrexate has a shorter onset of action in this setting. METHODS Patients with chronic active Crohns disease were admitted to this investigator-blind study. Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months, with at least one attempt to discontinue treatment. The disease had to be clinically active at entry, with a Crohns Disease Activity Index of > or = 200. Six patients treated with azathioprine and methotrexate, respectively, were found to have enterocutaneous and perianal fistulas. At entry, all patients received prednisolone (40 mg once a day) which was tapered over a period of 12 weeks unless their clinical condition deteriorated. All patients were randomised to receive i.v. methotrexate 25 mg/week, or oral azathioprine 2 mg/kg per day, for a 6-month follow-up period. After the first 3 months, methotrexate was switched to oral administration maintaining the same dose. The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy. Clinical remission was defined as the lack of need for steroid treatment and a Crohns Disease Activity Index score of < or = 150 points at each scheduled visit. RESULTS In the 54 patients (26 F, 28 M, mean age 34 years, range 18-60) randomly assigned to methotrexate (n=27) or azathioprine (n=27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 (methotrexate 44%, azathioprine 33%, p=0.28, (95% CI, 0.369-0.147), and 6 months (methotrexate 56%, azathioprine 63%, p=0.39, 95% CI, 0.187-0.335), respectively. Six patients withdrew from therapy due to adverse events: 3/27 (11%) in methotrexate and 3/27 (11%) in azathioprine. Drug-related adverse events (asthenia, nausea and vomiting) that did not require withdrawal from therapy were more frequent in the methotrexate group (azathioprine: 2/27 (7%); methotrexate: 12/27 (44%), p=0.00009). The frequency of these adverse events was comparable during the intravenous or oral administration of the drug. CONCLUSIONS This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohns disease, therapeutic efficacy being comparable, but not faster, than that of azathioprine.

Perianal Fistulae Following Infliximab Treatment Clinical and Endosonographic Outcome

BackgroundManagement of perianal and rectovaginal fistulae complicating Crohn’s disease (CD) is unsatisfactory. Infliximab is effective in the treatment of fistulating CD. However, reopening of fistulae is frequent, suggesting the persistence of deep fistula tracts despite superficial healing. In this study, the clinical and endosonographic behavior of perianal fistulae were evaluated following infliximab infusions, as well as the role of anal endosonography (AE) in predicting their outcome. MethodsThirty CD patients presenting with perianal and/or rectovaginal fistulae received an infusion of infliximab at a dose of 5 mg/kg at weeks 0 (entry into the study), 2, and 6. Laboratory and clinical assessments were repeated at same intervals and at week 10. AE was performed at entry and at week 10. Thereafter, the perianal region was re-examined every 6 months, and patients were investigated regarding draining of the fistula in the previous months. ResultsFifteen patients (53.6%) showed closure of the fistulae at week 10, but only 5 patients had the fistula tracts disappeared at AE. Clinical and AE closure of rectovaginal fistulae was less prevalent than that of perianal fistulae [14.3% versus 63.6% at week 6 (p = 0.035); 28.6% versus 59.1% at week 10 (p = 0.21); 14.3% versus 22.7% at AE (p = 1.00)]. The behavior of fistulae was not affected by their number and AE classification, presence of rectal disease, or setons. Twenty patients with perianal fistulae were followed for a median of 15.5 months. Patients with closed perianal fistulae at week 10 and disappearance of fistulae tract at AE showed a lower relapse rate than those with endosonographic persistence of fistula tract. ConclusionsInfliximab can heal perianal and rectovaginal fistulae in approximately 60% and 30% of patients, respectively. Despite closure, most fistula tracts are still detectable at AE. Persistence of the internal tract is a condition at higher risk of fistula recurrence.

Sonographic prevalence of liver steatosis and biliary tract stones in patients with inflammatory bowel disease: study of 511 subjects at a single center.

Goals: Inflammatory bowel diseases (IBDs) are associated with pathologic findings in the liver and biliary tract. Ultrasonography (US) represents a noninvasive means to study hepatobiliary abnormalities. This study evaluated the prevalence of US hepatobiliary changes and their relationship to clinical variables in a large IBD patient population followed in a single center. Study: Five hundred eighty‐three consecutive IBD patients were studied with US. After excluding patients with preexisting acute or chronic hepatitis, metabolic disorders, or obesity, 511 patients were investigated for age, duration, site, and severity of the disease, history of surgery, and present medical treatment. At US, liver size, echogenicity (graded as mild‐to‐moderate or severe indicating a corresponding degree of hepatic steatosis), focal lesions of the liver and gallbladder, and biliary tract abnormalities were recorded. Results: Three hundred eleven patients with Crohn disease (CD) and 200 patients with ulcerative colitis (UC) were recruited for the study. Hepatobiliary abnormalities were found at US in 54.2% and 55.9% of CD and UC patients, respectively. Liver enlargement and mild‐to‐moderate to severe liver steatosis were found in 25.7% and 39.5% of CD patients and in 25.5% and 35.5% of UC patients, respectively, a higher prevalence than among healthy controls (P < 0.001). The prevalence of gallstones among CD patients was 11%, higher than that among UC patients (7.5%) and controls (5.5%) (P = 0.016). The higher risk of gallbladder stones in CD was related to age, female sex, and previous surgery. Conclusion: The prevalence of liver enlargement and liver steatosis was higher among IBD patients. The prevalence of gallstones was increased in CD patients only. This risk was related to age, female sex, and previous surgery.

Infliximab-induced lupus in Crohn's disease: a case report

An 18-year-old male patient was under treatment with infliximab at a dose of 5 mg/kg at Weeks 0, 2 and 6 for refractory Crohns disease. In June 2002, the patient was admitted to the Outpatient Clinic of the Rheumatology Unit for arthralgia affecting the small joints, non-pruritic crops of purple skin lesions and malar rash in the face. Serum antinuclear antibodies were positive (1:640 speckled pattern), and anti-double-stranded DNA was positive (1:80); moreover, positivity of anti-extractable nuclear antigen was observed. Antihistone antibodies, lupus anticoagulant and anticardiolipin antibodies were negative. A diagnosis of infliximab-induced lupus was made and the drug treatment was withdrawn. However, 3 months after withdrawal of treatment, the patient still showed clinical and laboratory symptoms of systemic lupus erythematosus. After 6 months of treatment, systemic lupus erythematosus-related symptoms disappeared and anti-double-stranded DNA returned to normal. The patient is currently under treatment with prednisone 20 mg/day for systemic lupus erythematosus and with oral mesalazine 2.4 mg/day for Crohns disease. Treatment with infliximab is known to produce an increase of autoantibodies (antinuclear antibodies, anti-double-stranded DNA), but not clinical disease. This is the first case, to our knowledge, of onset of prolonged infliximab-induced lupus.

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

Crohns 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 46] 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-α, IFN-γ) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-α 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-γ (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-α 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.

Infliximab in treatment of Crohn's disease: the Milan experience

BACKGROUND Efficacy of infliximab in treatment of patients with moderate-to-severe refractory and fistulizing Crohns disease has been shown in controlled clinical trials. Moreover, audit data from North America and North Europe have confirmed efficacy in clinical practice comparable to that in clinical trials. AIM To report clinical experience using infliximab in treatment of Crohns disease in Italy, comparing efficacy and safety with those reported in clinical trials and other published series. PATIENTS AND METHODS The study population comprised 63 patients (31 males and 32 females, median age 33 years) treated with infliximab for refractory/inflammatory (31 patients) and/or fistulizing Crohns disease (32 patients). All patients received an infusion of infliximab at a dose of 5 mg/kg at weeks 0, 2 and 6. After the first infusion, clinical and laboratory assessments were repeated at weeks 2, 6 and 10. For refractory inflammatory Crohns disease, clinical remission was defined as a Crohns Disease Activity Index of < or = 150 at each scheduled visit, clinical response as a reduction in the Crohns Disease Activity Index score of > or = 70 points in comparison to baseline. For fistulizing Crohns disease, a complete response was defined as closure of any draining fistulae at week 10. A fistula was defined as closed when it no longer drained despite gentle finger pressure. A partial response was defined as reduction in number, size or drainage of fistulae, at the same visit. RESULTS According to an intention-to-treat evaluation on the 31 patients with refractory/inflammatory Crohns disease, at week 2, 42.5% (14 patients) had a clinical response and 31.3% of patients (10 patients) were in clinical remission. At week 10 (4 weeks after the end of third infusion), 80.6% (25 patients) had a clinical response and 71% (22 patients) were in clinical remission and 14/19 (74%) had discontinued steroid treatment. Of the 32 patients with fistulizing Crohns Disease, 15 (46.9%) had a complete response, 8 (25%) a partial response, and 9 (28.1%) no response at week 10 check-up. The incidence of side-effects was low (16%) and not influenced by concurrent immunomodulatory therapy. CONCLUSION The present experience with infliximab in clinical practice confirms its efficacy, in particular in inflammatory/refractory Crohns disease and its safety, at least, in short-term follow-up.

Ultrasonographic features of long-standing primary intestinal lymphangiectasia

This article describes a case of primary intestinal lymphangiectasia associated with protein-losing enteropathy and lower right leg lympoedema in a 20-year-old woman. Echographic findings showed dilation of the intestinal loops, regular and diffuse thickening of the walls, plical hypertrophy and impressive mesenteric oedema. Although diagnosis of the disease is substantially histological, the ultrasonographic characteristics of the lesions are fairly indicative and of certain diagnosis usefulness in patients with protein-losing enteropathy.

Effects of Helicobacter pylori eradication on gastric function indices in functional dyspepsia. A prospective controlled study.

BACKGROUND To date, it is unclear whether Helicobacter pylori infection is associated with disturbances of gastric emptying or acid secretion in patients with functional dyspepsia (FD). Our aim was to investigate whether, in the long run, cure of H. pylori infection significantly influences gastric emptying of solids, acid secretion, and gastrin and pepsinogen I (PGI) release in patients with FD. METHODS Thirty-eight consecutive H. pylori-positive patients with FD, whose complaints were scored for severity and frequency on the basis of a validated symptom questionnaire, were initially enrolled in the study. They were randomized to receive an eradicating regimen consisting of omeprazole plus clarithromycin and tinidazole for 1 week or full-dose ranitidine for 3 weeks. In 33 patients (18 H. pylori-cured and 15 with persistent infection) basal and pentagastrin-stimulated acid secretion, fasting and meal-induced gastrin concentrations, fasting serum PGI levels, and gastric emptying of solids were determined before and 6 months after therapy. RESULTS In the 18 H. pylori-cured patients meal-induced gastrin and fasting PGI levels were significantly reduced after 6 months as compared with pretreatment values (peak serum gastrin, 76.0 +/- 23.4 versus 111.9+/-37.4 pg/ml; PGI, 57.1+/-23.4 versus 72.9+/-29.1 ng/ml), whereas they remained virtually unchanged in the 15 patients with persistent infection. In contrast, both basal and stimulated acid secretion and gastric emptying time of solids remained unmodified over time in both groups of patients. CONCLUSIONS We confirm that also in patients with functional dyspepsia H. pylori eradication in the long run significantly reduces gastrin and PGI release as a result of improvement in the underlying antral gastritis, but this is not accompanied by modifications of gastric emptying of solids or acid secretion.

Efficacy of Lansoprazole in the Short- and Long-Term Treatment of Gastro-Oesophageal Reflux Disease

SummaryThe aim of this survey was to systematically overview clinical studies, published in the English literature, regarding the treatment of reflux oesophagitis with the newly developed proton pump inhibitor (PPI) lansoprazole, compared with other acid suppressant drugs. A total of 11 studies were identified in the literature and included in the overview; of these, four studies compared lansoprazole with ranitidine, one with famotidine and four with the PPI omeprazole. Two studies focused exclusively on the comparison of different dosages of lansoprazole. This overview showed that, with regard to healing rate and symptomatic relief, lansoprazole was superior to H2 receptor antagonists. Regarding healing rates and symptom response, lansoprazole was equal to omeprazole. The few data concerning long-term treatment indicated similar efficacy for the two PPIs. The tolerability of lansoprazole did not appear to be different to H2 receptor antagonists and omeprazole.

Visceral Hypersensitivity Is Not a Feature of Fibromyalgia Syndrome

Objective: Visceral hyperalgesia is commonly observed in irritable bowel syndrome [IBS], a common cause of comorbidity with fibromyalgia syndrome [FMS]. The aim of this study was to evaluate in patients affected by FMS the presence of IBS-like symptoms and of visceral hyperalgesia. Methods: Twenty-seven FMS patients were studied and compared with 32 IBS patients for visceral hyperalgesia by the anorectal balloon distension test. Results: Eighteen [66%] of FMS patients fitted the Rome criteria for IBS. Patients with IBS presented lower than normal thresholds for the sensation of urgency and pain [P < 0.05], whereas the sensation of gas present in the rectum and of desire of defecation were not statistically different from normals. On the contrary, patients with FMS, either with or without IBS-like symptoms, presented values similar to normals for all the examined thresholds [P > 0.05]. Conclusions: Our study confirms that IBS symptoms are present in a relevant proportion of FMS patients, and that the majority of IBS patients present a condition of visceral hypersensitivity, as induced by a rectal balloon distension test. Patients with FMS, however, do not present this feature. The reason why FMS patients frequently have IBS-like symptoms with a normal visceral hypersensitivity remains elusive.