R. Sostegni

Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up.

Severe ulcerative colitis is a life‐threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy.

Anti-tumour necrosis factor alpha (Infliximab) in the treatment of severe ulcerative colitis: result of an open study on 13 patients

BACKGROUND Conventional treatment options for patients with severe steroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit from anti-tumour necrosis factor alpha (Infliximab) therapy in patients with steroid refractory ulcerative colitis. AIM To evaluate the efficacy of Infliximab in the treatment of severe ulcerative colitis refractory to conventional therapy PATIENTS AND METHODS A series of 13 patients with severe ulcerative colitis, refractory to therapy with methyl-prednisolone, 60 mg daily for seven or more days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. RESULTS AND CONCLUSIONS Of these 13 patients, 10 (77%) had a clinical response to therapy defined by a clinical activity index 10 on two consecutive days. In 2 patients (15%) total colectomy was necessary on account of clinical worsening whilst one patient refused surgery and was lost to follow-up. All patients who responded showed very rapid clinical improvement, within 2 to 3 days of infusion. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 10.1 months (range 5-12; during this time, 9 out of 10 patients (90%) maintained clinical remission and were able to discontinue corticosteroid therapy. Infliximab appears to be an effective agent for inducing long-standing remission in refractory patients with severe ulcerative colitis.

Infliximab and the risk of latent viruses reactivation in active Crohn's disease

Background: Infliximab is used for refractory Crohns disease but there are concerns regarding long‐term safety. Recently, JC‐polyomavirus (JCV) was studied after 3 cases of progressive multifocal leukoencephalopathy (PML) were found after treatment with natalizumab. The aim of this study was to investigate the short‐term effect of infliximab on reactivation of several harmful latent viruses. Methods: Sixty consecutive patients scheduled for infliximab induction course were prospectively enrolled. Blood samples were taken before each infliximab infusion at 0, 2, 6, and 14 weeks. Specific polymerase chain reaction (PCR) analyses were performed to detect JCV, Epstein–Barr virus (EBV), human herpes virus‐6, (HHV‐6), ‐7, ‐8, and cytomegalovirus (CMV). Results: Indications to infliximab were luminal and fistulizing disease in 49 and 15 cases, respectively. Clinical improvement and remission were achieved in 54 (90%) and 39 (65%) of patients, respectively, at 6 weeks. No patient was JCV‐positive at any timepoint. EBV serology was positive for 59/60 patients (98%); EBV‐PCR tests were transiently positive (>40 copies/105 Peripheral blood mononuclear cells, PBMC) in 4 (7%) patients after infliximab, but in each case were negative at subsequent timepoints. All patients were negative for HHV‐6, ‐7, and ‐8 at all timepoints. CMV serology was positive in 42 patients (70%), but no CMV‐PCR‐positive patient was observed. There was no association between concomitant treatments or clinical characteristics and viral status. Conclusions: Our results support the safety of short‐term infliximab treatment with respect to latent virus reactivation. The long‐term effects of infliximab, particularly for the issue of lymphoproliferative disorders, warrants further studies with larger populations, but so far data are reassuring. (Inflamm Bowel Dis 2007)

Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial

OBJECTIVES:The aims of this long-term, prospective randomized study were to evaluate the clinical usefulness of α-interferon in treating chronic HBV infection and to establish whether clearance of viral replication markers and normalization of liver function tests induced by α-interferon were sustained.METHODS:Sixty-four patients with chronic wild type (HBeAg-positive) hepatitis B, enrolled between 1983 and 1987, were randomized into two groups. Thirty-three patients received α-interferon (5 MU/m2 three times weekly for 6 months; treated group), and 31 were not treated (controls). Treated and control patients were prospectively followed for a mean of 86.4 ± 6.96 and 79.7 ± 6.8 (p= NS) months, respectively.RESULTS:Clearance of the following viral markers was found in treated and control patients as follows: HBV-DNA, 26 (78.9%) and 18 (58.1%) (p= 0.106); HBeAg, 30 (90.9%) and 19 (61.2%) (p < 0.007); and HBsAg, 12 (36.4%) and three (9.8%) (p < 0.017). Persistent abnormal ALT levels were found in 11 (33.3%) treated and in 22 (70.9%) control patients (p < 0.025). Four control and three treated patients developed portal hypertension whereas two control and one treated patient developed hepatocellular carcinoma. Seven patients (five treated and two controls) were retrospectively found to have hepatitis C virus (HCV) coinfection before enrollment. To date, all coinfected patients remain positive for HCV-RNA. Also, all HCV coinfected patients, except one in the treated group, had persistent increased serum ALT levels. One of the coinfected patients developed portal hypertension.CONCLUSIONS:Chronic HBV hepatitis patients responding to interferon treatment had a faster, more complete, and sustained clearance of viral markers than controls; HCV coinfection does not seem to negatively affect the clearance of HBV replicative markers. However when coinfection occurs, hepatic disease persists despite HBV marker clearance.

The natural history of ulcerative proctitis: a multicenter, retrospective study

Abstract OBJECTIVE: The aim of this study was to evaluate the clinical features and the long term evolution of patients with a well defined initial diagnosis of ulcerative proctitis. METHODS: Patients with an original diagnosis of ulcerative proctitis who had been seen at any of 13 institutions from 1989 to 1994 were identified. Data on disease onset and subsequent evolution were recorded. In addition, 575 patients with more extensive disease, treated in the same centers, were used as controls. RESULTS: A total of 341 patients satisfied the inclusion criteria. The percentage of smokers in these patients was slightly lower than in controls; no differences were found in the other clinical/demographic variables evaluated. A total of 273 patients entered long term follow-up (mean, 52 months). Proximal extension of the disease occurred in 74 of them (27.1%). The cumulative rate of proximal extension and of extension beyond the splenic flexure was 20% and 4% at 5 yr and 54% and 10% at 10 yr, respectively. The risk of proximal extension was higher in nonsmokers, in patients with >3 relapses/yr, and in patients needing systemic steroid or immunosuppressive treatment. Refractory disease was confirmed as an independent prognostic factor at multivariate analysis. CONCLUSIONS: Proximal extension of ulcerative proctitis is frequent and may occur even late after the original diagnosis. However, the risk of extension beyond the splenic flexure appears to be quite low. Smoking seems to be a protective factor against proximal extension, whereas refractoriness is a risk factor for proximal extension of the disease.

Abdominal pain and bowel dysfunction : diagnostic role of intestinal ultrasound

Background Abdominal pain and irregular bowel habits are common among young people. Irritable bowel syndrome is frequent in the general population and has important economic and social costs. Inflammatory bowel diseases are chronic processes with an acute or indolent onset in young people. Differential clinical diagnosis between irritable bowel syndrome and inflammatory bowel disease can be difficult since symptoms and signs are often non-specific. Objective To evaluate the role of intestinal ultrasound, a non-invasive, simple and cheap diagnostic tool, in the differentiation between organic and functional bowel diseases. Methods Abdominal and intestinal ultrasound examinations were performed on 313 consecutive outpatients presenting with abdominal pain and irregular bowel habits lasting more than 3 months. These patients had no symptoms or signs indicative of organic disorders and no previous diagnosis of organic disease. An intestinal wall thickness of more than 7 mm was considered diagnostic for inflammatory bowel disease. Subsequently, we compared the ultrasound results with diagnoses obtained following the traditional criteria (radiological and endoscopic examinations). Results Intestinal ultrasound for the diagnosis of inflammatory bowel disease showed 74% sensitivity, 98% specificity, a positive predictive value of 92% and a negative predictive value of 92%. Conclusions In our experience, intestinal ultrasound seems important as a first diagnostic tool in young patients without clear symptoms or signs of organic diseases, and can be used as an indication that subsequent invasive tests are required.

Abdominal bowel ultrasound can predict the risk of surgery in Crohn's disease : Proposal of an ultrasonographic score

Objective. Abdominal bowel ultrasound (US) is widely used in the management of Crohns disease (CD). The aim of this study was to evaluate the prognostic role of bowel-wall US morphology on the short-term risk of surgery. Material and methods. The 147 CD patients recruited in a case-control study comprised 49 cases operated on within 30 days after US examination and 98 matched non-operated controls. Clinical and US characteristics were analysed. Bowel-wall thickness was recorded, bowel-wall patterns were grouped into five types, but for final analysis they were grouped as “preserved” or “disrupted stratification”. Results. Wall thickness and US patterns were significantly different between cases and controls (p<0.0001). A wall thickness >4.5 mm was observed in 45/49 cases and 47/98 controls (OR = 12.21), while “disrupted stratification” was observed in 34/49 cases and 12/98 controls (OR = 16.24). Among the clinical and US characteristics recorded, only 4 US variables were independently associated with surgery (pattern, thickness, presence of fistulae/abscesses and stenoses) and considered for the US score=(2.5*US pattern)+(1.5*Bowel thickness)+(3*Presence of fistulae/abscesses)+(1.5*Presence of stenoses). Based on this score, up to 84% of patients were correctly classified according to actual status (operated/non-operated). Conclusions. Although it needs further prospective validation, the score we propose seems to be a reliable prognostic marker for the short-term risk of surgery in CD. In particular, the score points out those patients with an impending risk of surgery who need careful and frequent control in order to decide on the right time for surgery.

Medical treatment of severe ulcerative colitis

Approximately 15% of patients with ulcerative colitis have a severe attack requiring hospitalization at some time during their illness. This treatment leads to a remission in 60–80% of patients and non‐responders may require a total colectomy. Mortality in severe episodes of ulcerative colitis decreased from 31–61% in the 1950s to 5–9% in the 1960s thanks to the introduction of steroids and to a policy of early colectomy. Recently, some new drugs have been shown to be effective in the treatment of severe steroid‐refractory ulcerative colitis. This review concentrates on the clinical evaluation, prognostic factors and new developments in medical therapy in severe ulcerative colitis. A retrospective evaluation of a consecutive series of patients with severe ulcerative colitis admitted to a Gastroenterology Department in Torino, Italy, is also reported.

The use of methotrexate for treatment of inflammatory bowel disease in clinical practice

BACKGROUND Methotrexate is considered a treatment for Crohns disease, whilst few data in ulcerative colitis are available. AIM To evaluate frequency, indications, efficacy and safety of methotrexate in inflammatory bowel disease patients. METHODS 5420 case histories were reviewed. RESULTS Methotrexate was prescribed to 112 patients (2.1%; 89 Crohns disease, 23 ulcerative colitis). It was the first-line immunosuppressive option in 32 (28.6%), it was an alternative drug due to toxicity or failure of thiopurines in 80 (71.4%). Steroid-dependence represented the main indication both when it was used as first (13/32, 40.6%) and second option (41/80, 51.2%). Efficacy was considered optimal in 39/112 (34.8%), partial in 29/112 (25.9%), absent in 22/112 (19.6%), not assessable in 22/112 (19.6%). Side effects happened in 49 out of 112 patients (43.7%) (39 Crohns disease, 10 ulcerative colitis), leading to drug discontinuation in 38 (33.9%). The occurrence of side effects was approximately fivefold higher in patients who did not receive folic acid (14/19, 73.7%) than in those who did (35/93, 37.6%): odds ratio 4.64, 95% confidence interval 1.54-14.00; p=0.005. CONCLUSIONS The use of methotrexate appears to be negligible in clinical practice. However, our results suggest that, if appropriately used, methotrexate could be more widely administered to inflammatory bowel disease patients with complicated disease.

Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: Early and late outcome and predictors of colectomy

BACKGROUND Infliximab is effective as rescue therapy in severe corticosteroid-refractory ulcerative colitis. The optimal dose regimen and the long term benefits are not well defined. The aim of the present study was to evaluate short- and long-term colectomy rate in a cohort of patients with severe corticosteroid-refractory ulcerative colitis who received a three-dose infliximab induction regimen. METHODS One hundred and thirteen patients admitted to 11 Italian IBD referral centres and treated with infliximab according to an intention to treat three-dose regimen were included. The co-primary endpoints were 3- and 12-month colectomy rate. The secondary end-points were the overall colectomy-free survival and the identification of predictors of colectomy. RESULTS The 3- and 12-month colectomy rates were 18.6% (95%CI 11.8%-26.9%) and 25.6% (95%CI 17.9%-34.7%) respectively. High CRP values and severe endoscopic lesions were associated with the risk of colectomy: Risk Ratio (RR)=2.15 (95%CI 1.05-4.36), and RR=5.13 (95%CI 1.55-16.96), respectively. In patients escaping early colectomy, the probability of a colectomy-free course at 12, 24, 36 and 60months was 91%, 85%, 81% and 73%, respectively. Endoscopic severity was the only predictor of long term colectomy (RR=7.0; 95%CI 1.09-44.7). Adverse events occurred in 16 patients (14%); there was one death (0.88%) due to pulmonary abscess. CONCLUSIONS Infliximab is an effective and safe rescue therapy for severe corticosteroid-refractory ulcerative colitis. A three-dose induction regimen seems to be the treatment of choice for preventing early colectomy. Severe endoscopic lesions appear to be predictor of short- and long-term colectomy.