Infliximab for ulcerative colitis

Hepatocellular carcinoma - History, current status and perspectives

23Patzer JF. Advances in bioartificial liver assist devices. Ann NY Acad Sci 2001;944:320-33. 24Chang M, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336: 1855-9. 25 Ikeda K, Saito S, Koida I, Arase Y, Tsubota A, Chayama K, et al. A multivariate analysis of risk factors for hepatocellular carcinoma: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993; l&47-53. 26Seeff LB, Hollinger B, Alter H, Wright GC, Cain CMB, Buskell ZJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a national heart, lung and blood institute collaborative study. Hepatology 2001;33:455-63. *’ Barrett S, Goh J, Coughlan B, Ryan E, Stewart S, Cockram A, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogeneous cohort spontaneous viral clearance and chronic HCV infection. Gut 2001;49:423-30. 28Wiese N, Berr WM, Porst LM, Oessen U for the East German

COMMENTARY

lnfliximab J. Simmons,

Hepatitis C Study Group. Low frequency of cirrhosis in a hepatitis C (genotype lb) single-source outbreak in Germany: a 20-year multicenter study. Hepatology 2000;32:91-6. 29Yu SZ. Primary prevention of hepatocellular carcinoma. J Gastroenterol Hepatol 1995;10:673-82. ” Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomized trial of effects of interferon-a on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051-5. 3’Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhosis and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 1999;131:174-81. 32Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;344:1561-7.

DIGESTLIVER tttti 2002;34:616-8

for ulcerative

colitis

D.l? JewelF

The action of tumour necrosis factor (TNF) is diverse and has been implicated in many pathological processes and disease states; it is thought to be one of the key cytokines involved early in the inflammatory cascade. TNF seems central to the pathogenesis of inflammatory bowel disease (IBD) and in particular Crohn’s disease (CD). Elevated levels of TNF are detected in the inflamed mucosa in IBD * and changes in mucosal TNF levels, over time, can predict future clinical relapse *. A chimaeric monoclonal antibody raised against TNF, infliximab, has proven to be an effective therapy in patients with CD and has also proven to be useful both in steroid resistant active disease and in those with fistulas 3-5.This represents the first step towards more rational specific therapies for IBD, which have traditionally involved non-specific anti-inflammatories and immunosuppressives. Following this remarkable success in treating CD with infliximab, a number of groups have investigated the effect of this agent in patients with refractory ulcera-

tive colitis (UC). Though TNF is classically seen as a Thl cytokine involved in the pathogenesis of CD, a number of lines of evidence suggest that TNF may also be important in the pathogenesis of UC. Increased levels of TNF have been detected in the intestinal mucosa, stool, rectal dialysate and in the plasma of patients with active UC. The cotton-top tamarin is probably the closest animal model of UC, spontaneously developing severe diarrhoea and wasting, which responds to corticosteroids. The pathology of this colitis closely mimics the chronic inflammation seen in UC and these animals also develop the complications of UC, such as colonic adenocarcinoma. TNF levels are increased in these animals and treatment with a chimaeric monoclonal antibody to TNF (CDP571) led to an improvement in symptoms and weight gain 6. The first study to examine the effects of anti-TNF therapy in UC used the CDP571 antibody and was published by Evans et al. in 1977 7. They enrolled 15 patients with mild to moderate UC of whom most had left-sided rather than extensive disease and only 6 were described as steroid-resistant. Patients were followed for 8 weeks following a single infusion of antibody.

Commentaries

Modest but significant reductions were observed in Powell-Tuck activity score, erythrosedimentation rate (ESR) and C reactive protein (CRP). However these effects were short-lived and failed to remain significant after 2 weeks. Two further reports of the use of infliximab in UC were published in peer-reviewed journals last year. Chey et al. 8 describe an open study of 8 patients with severe UC, treated with a single infusion of infliximab (5 mg/kg) and followed for 8 weeks. O f these, 3 had extensive UC and 5 left-sided disease, 5 were taking 6-mercaptopurine and 5 had failed to respond to parenteral steroids. All patients made a good response, with significant reductions in clinical activity index (CAI) at one week, and histological score at one, four and eight weeks. No subsequent relapses were reported but the length of follow-up was not stated. Sands et al. 9 describe eleven patients enrolled in a randomized double blind placebo controlled trial of infliximab (5, 10 and 20 mg/kg) in patients with severe UC as defined by the Truelove and Witts criteria (median score 12). All patients had failed to improve, in hospital, on parenteral steroids, two patients were taking immunosuppressives and no patient had received cyclosporin in the previous 3 months. In the infliximab-treated group, reductions were observed in the CAI, sigmoidoscopic score and laboratory markers including CRP and interleukin-6 (IL-6). O f the 3 placebo-treated patients, none were considered a treatment success, 2 underwent urgent colectomy and one elective colectomy. O f the 8 infliximab-treated patients, 4 were considered a treatment success and, of the 4 treatment failures, one was treated with cyclosporin and one underwent colectomy. No serious adverse events were described in either study. Two further studies are presented in this issue of the journal (Digest Liver Dis 2002;34:626-30 and 631-4). Both are open studies of steroid refractory patients treated with infliximab at the standard dose of 5 mg/kg; both report the outcome of a more prolonged period of follow-up. Actis et al. lo report on 8 patients with severe UC, of whom 4 had total colitis, 1 subtotal, and 3 left-sided disease. Six patients had failed to respond to 7 days of parenteral steroids at maximum dose, and one further patient had not responded to prednisolone 50 mg for 2 weeks. Four patients did not respond to infliximab and underwent urgent colectomy. The 4 responders were followed for between 1 and 7 months. One patient relapsed rapidly and underwent colectomy. The remaining 3 patients were treated with azathioprine (2 mg/kg), with 2 patients maintaining remission off steroids and the remaining patient having a clinical relapse at 6 months which was treated with a further infusion of infliximab. Thus the initial response rate was 50% and the sustained response rate 25%. Kohn et al. ” describe 13 patients receiving infliximab

for severe UC, unresponsive to parenteral steroids (methyl prednisolone 60 mg) after 7 days. In total, 10 patients responded to infliximab with meaningful reductions in CA1 (14/21 to 5.4/21, response defined at CA1 510) at 2 weeks. Two non-responders underwent urgent colectomy and one was lost to follow-up. O f the 10 responders, all were able to withdraw from steroids and 7 were maintained on immunosuppressives. One patient relapsed after 5 months. A number of other series have recently been reported in abstract form. A group from Milwaukee, USA reported results from 12 children and 15 adults with either fulminant or chronically active UC 12.Complete response, defined as steroid cessation, was observed in 4/5 children and 2/5 adults with fulminant disease but none of the patients with chronic active disease had a complete response. Those with only a partial response (3/ 12 children and 9/ 15 adults) were very likely to undergo colectomy in the subsequent 6 months. Another American group reported a good response at 2 weeks in 5/5 paediatric cases treated with infliximab 13.The preliminary results of a multi-centre blinded randomised controlled trial involving steroid refractory patients from the UK were also reported. Remission was no more likely in the infliximab-treated group compared to the placebo group at both 2 and 6 weeks (3122 vs l/20 and 5/22 vs 6/20, respectively). In 20 non-responders given a second infusion of infliximab, only 4 out of the 19 evaluated, achieved remission 14. The obvious difficulty in interpreting these reports is that all involve small numbers and all but 2 are open case series. Details regarding the condition, history and medical treatment of each of the patients involved are incomplete - it is very difficult to know whether we are comparing patients who are alike. Nevertheless, given these limitations, it is still possible to produce some overall conclusions - infliximab does not seem to be particularly effective in patients with mild to moderate UC or those with chronic active steroid-resistant disease. The treatment successes seem to be in the hospitalised patients with fulminant or acute severe UC who do not settle on conventional high dose parenteral steroids. In this group, the initial remission rate is of the order of 50-75%, though with a lower sustained remission rate. Response is usually seen very quickly, within 48-72 hours. The response rate with infliximab in acute severe UC is similar to that seen with intravenous cyclosporine, with rates ranging from 56% to 81% r5-17.Infliximab seems to be well tolerated in the short-term compared to cyclosporine which has frequent adverse effects such as parasthesiae, tremor, hypertension and reversible renal impairment. The longer-term adverse effects of infliximab are not yet fully established and we must still be cautious - in a series of 217 infliximab treated patients 617

Commentaries

from Sweden, 6 deaths were reported including 2 cases of lymphoma and 3 fatal infections 18.In none of the reported series were patients treated acutely with both cyclosporine and then with infliximab if cyclosporine failed. In Oxford, we have successfully treated 3 such patients who failed to respond to both intravenous steroids and cyclosporine. Despite these reservations, the use of infliximab in patients with acute severe UC that fails to respond to high dose iv steroids shows promise, and larger controlled trials, possibly comparing infliximab with cyclosporine should be considered. We must not forget, however, that we currently have a safe curative treatment for severe UC and we should not dismiss the role of surgery. Mortality should be 3% or less for an urgent colectomy r9, and this must be weighed against the risks of malignancy and opportunistic infection in profoundly immunosuppressed patients treated aggressively with these newer medical therapies. List of abbreviations CAI: clinical activity index; CD: Crohn’s disease; CRP: C reactive pro.7 tein; ESR: erythrosedimentation rate; HI: inflammatory bowel disease: TNF: tumour necrosis factor; UC: ulcerative colitis. -. -I Rddms for correspondence Gastroenterology Department, Royal Berkshire Hospital, Reading, Berkshire RGI SAN; ’ Gestroenterology Unit, Radcliffe Infirmary, Oxord OX2 6HE, UK

References I Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997;40:443-8. * Schreiber S, Nikolaus S, Hampe J, Hamling J, Koop I, Groessmer B, et al. Tumour necrosis factor alpha and interleukin lbeta in relapse of Crohn’s disease. Lancet 1999;353:459-61. 3 D’Haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s distrial. Gastroenterology ease: A European multicenter 1999;116:1029-34. 4 Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Van Hogezand R, et al. Infliximab or the treatment of fistulas in pa-

tients with Crohn’s disease. N Engl J Med 1999;340:1398-405. 5 Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997;337:1029-35. 6 Watkins PE, Warren BF, Stephens S, Ward P, Foulkes R. Treatment of ulcerative colitis in the cotton-top tamarin using antibody to tumour necrosis factor alpha, Gut 1997;40:628-33. ’ Evans RC, Clarke L, Heath P, Stephens S, Morris AI, Rhodes JM. Treatment of ulcerative colitis with an engineered human antiTNF-alpha antibody CDP57 1. Aliment Pharmacol Ther 1997;11:1031-5. ’ Chey WY, Hussain A, Ryan C, Potter GD, Shah A. Infliximab for refractory ulcerative colitis. Am J Gastroenterol 2001;96:2373-81. 9 Sands BE, Tremaine WJ, Sandbom WJ, Rutgeerts PJ, Hanaver SB, Mayer L, et al. Infliximab in the treatment of severe, steroidrefractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001;7:83-8. lo Actis GC, Bruno M, Pinna-Pintor M, Rossini FP, Rizzetto M. Infliximab for treatment of steroid-refractory ulcerative colitis. Digest Liver Dis 2002;34:631-4. ” Kohn A, Prantera C, Pera A, Cosintino R, Sostegni R, Daperno M. Anti-tumour necrosis factor alpha (Infliximab) in the treatment of severe ulcerative colitis: result of on open study on 13 patients. Digest Liver Dis 2002;34:626-30. I2 Kugathasan S, Prajpati D, Kim J, et al. Infliximab outcome in children and adults with ulcerative colitis. Gastroenterology 2002;122:A615. Ii Oliva-Hemker M, Roper S, Cuffari C, Liebowitz L. Infliximab therapy for paediatric ulcerative colitis. Gastroenterology 2002;122:A616. I4 Probert C, Hearing S, Schreiber S, et al. Infliximab in steroid resistant ulcerative colitis: a randomised controlled trial. Gastroenterology 2002;122:A99. I5 D’Haens G, Lemmens L, Geboes K, Vandefutte L, Van Acker F, Mortelman L, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis, Gastroenterology 2001; 120: 1323-9. I6 Hyde GM, Thillainayagam AV, Jewel1 DP. Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? Eur J Gastroenterol Hepatol 1998; lo:41 l-3. I7 Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336: 16-9. Iy Ljung T, Janzewska 1, Karlen P, et al. Infliximab in inflammatory bowel disease: efficacy, surgical outcome, severe adverse events and mortality in clinical practice. First 217 patients in Stockholm county. Gastroenterology 2002; 122:A6 16. I9 Melville DM, Ritchie JK, Nicholls RJ, Hawley PR. Surgery for ulcerative colitis in the era of the pouch: the St Mark’s Hospital experience. Gut 1994;35:1076-80.