Clin J Gastroenterol (2009) 2:404–407 DOI 10.1007/s12328-009-0115-7
Successful treatment for pouchitis with rebamipide refractory to a combination of metronidazole (MNZ) and ciprofloxacin (CFX) Naotaka Ogasawara • Makoto Sasaki • Yasutaka Hijikata • Ryuta Masui • Satoshi Tanida • Takayoshi Kanematsu • Takeshi Kamiya • Hiromi Kataoka Takashi Joh • Kunio Kasugai
Received: 23 July 2009 / Accepted: 11 September 2009 / Published online: 16 October 2009 Ó Springer 2009
Abstract A 35-year-old male who had undergone proctocolectomy and ileo-anal pouch surgery (IPAA) because of ulcerative colitis presented with worsening diarrhea and hematochezia. Pouchitis was diagnosed, and he was prescribed with metronidazole (MNZ) and a betamethasone enema. However, his condition did not remarkably improve despite these strategies. Endoscopy revealed ulceration and inflammation in the ileal pouch together with contact bleeding and mucous discharge. He underwent granulocytapheresis (G-CAP) and was prescribed anal 5-aminosalicylic acid (5-ASA) and oral prednisolone. Oral azathioprine (AZA) and a combination of MNZ and ciprofloxacin (CFX) did not result in any improvement. He was then treated with rebamipide enemas twice daily for 8 weeks without additional drug therapy. Two weeks thereafter, stool frequency started to decrease, fecal hemoglobin became negative, and his symptoms gradually improved. Endoscopic findings after the rebamipide therapy showed that the ulcers in the ileal pouch had mostly healed without obvious inflammation and bleeding. Rebamipide was thus maintained throughout the therapeutic period and for 13 months of follow-up. Rebamipide effectively treated severe pouchitis that was
N. Ogasawara M. Sasaki (&) Y. Hijikata R. Masui K. Kasugai Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi 480-1195, Japan e-mail: [email protected]
S. Tanida T. Kanematsu T. Kamiya H. Kataoka T. Joh Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
refractory to intensive conventional medication including antibiotics and corticosteroids. Keywords Ulcerative colitis Ileo-anal pouch surgery (IPAA) Inflammatory bowel disease Rebamipide
Introduction Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that primarily affects the colon and the rectum, and can be complicated with rectal bleeding, diarrhea, fever, anemia and weight loss . Patients who are unresponsive to standard therapies have historically had no other choice but curative resection, such as colectomy . Accordingly, proctocolectomy and ileo-anal pouch surgery (IPAA) have become the standard choices of curative resection for patients with ulcerative colitis who require surgical removal of the colorectum . However, most patients frequently develop long-term complications such as pouchitis after curative IPAA [2, 3]. This complication probably represents a disease spectrum ranging from an acute, antibiotic-responsive entity to a chronic, antibioticrefractory disorder . The antibiotics metronidazole (MNZ) and ciprofloxacin (CFX) represent the first-line treatment for pouchitis. However, pouchitis typically does not respond to full-dose, single-agent antibiotic therapy. Possible causes include non-steroidal anti-inflammatory drug (NSAID) use [5, 6], concurrent infection with Clostridium difficile  or cytomegalovirus (CMV) [8, 9], celiac disease, cuffitis and Crohn’s disease (CD) . Colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) is effectively inhibited by rebamipide (2-(4chlorobenzoylamino-3-[2 (1H)-quinolinon-4-yl]-propionic acid), which promotes gastric ulcer healing by stimulating
Clin J Gastroenterol (2009) 2:404–407
local prostaglandin synthesis and mucosal epithelial cell regeneration via an increase in epithelial growth factor (EGF) and EGF receptor expression . Other investigators have described anti-inflammatory actions and suppression of neutrophil functions with rebamipide [11–13], and this is widely applied to treat gastric ulcers in Japan . Makiyama et al. [15, 16] recently administered rectal rebamipide enemas to treat complicating proctitis and described the first successful case study of rebamipide in a patient with IBD. Here, we describe severe refractory pouchitis that was treated with rebamipide, which promotes epithelial cell regeneration and angiogenesis.
Case report A 35-year-old male was diagnosed with UC in 1982 and treated with conventional medications including corticosteroids. However, the UC had become refractory to conventional medication and granulocytapheresis (G-CAP) by October 2001, and the patient underwent total colectomy with mucosal proctocolectomy (Fig. 1a), IPAA and ileostomy during November 2001. In February 2002, protracted symptoms of diarrhea and hematochezia had worsened, and colonoscopy revealed pouchitis. He was administered MNZ together with a betamethasone enema. However, this strategy did not result in any improvement. The fistula between the ileum and cutis was surgically removed in April 2004, and in July 2005 he underwent G-CAP (once weekly for 8 weeks), and anal 5-aminosalicylic acid (5-ASA) was administered (1 g/day for 37 weeks). By May 2006, oral prednisolone (15 mg/day for 3 weeks, 10 mg/day for 5 weeks, and 5 mg/day for 4 weeks) had not resulted in any improvement. Endoscopy in July 2006 revealed regional ulceration and inflammation of the ileal pouch together with
Fig. 1 Histological findings of ulcerative colitis (a) and pouchitis (b). a Proctocolectomy specimen shows surface epithelial irregularities, distorted crypt architecture, inflamed crypts with depletion of some goblet cells, crypt abscesses and lymphocytic infiltration of lamina
spontaneous bleeding and mucous discharge (Fig. 2). A biopsy specimen revealed severe infiltration of inflammatory cells and focal necrosis (Fig. 1b). Therefore, severe pouchitis was diagnosed based on the Japanese diagnostic criteria for pouchitis (JDCP), and the score was 14 on the pouchitis disease activity index (PDAI). Azathioprine (100 mg/day for 16 weeks) was administered in July 2006, followed by a combination of oral MNZ (750 mg/day for 5 weeks) and CFX (600 mg/day for 5 weeks) in December 2006. The patient’s symptoms then went into a relapseremission cycle without an increase in serum C-reactive protein (CRP) levels. The patient provided written informed consent in July 2007 to treatment with rebamipide enemas (rebamipide 150 mg, carboxymethyl cellulose 900 mg and physiological saline 60 ml/dose) twice a day for 8 weeks without additional drug therapy. Stool frequency started to decrease after 2 weeks of rebamipide therapy, fecal hemoglobin became negative, and his symptoms gradually improved. Endoscopic findings during August 2007 showed that the ulcers in the ileal pouch had mostly healed with no obvious inflammation, bleeding and mucous discharge. However, partial lack of vascular pattern, slight edema and a focal granular appearance persisted in the ileal pouch (Fig. 3). Therefore, he was diagnosed with mild pouchitis based on the JDCP. Rebamipide was thus maintained throughout the therapeutic period and for 13 months of follow-up, during which the pouchitis remained in remission with no adverse responses.
Discussion Although IBD has been recognized for many decades, the initiating and perpetuating factors have remained obscure. Patients with relapsed UC who are unresponsive to standard
propria. Therefore, active ulcerative colitis was diagnosed. b Ileal pouch biopsy specimen shows inflammatory cell infiltration and focal necrosis (a, b 9100)
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Fig. 2 Endoscopic findings of refractory pouchitis before rebamipide administration. Ulcers in ileal pouch are accompanied by regional ulceration, inflammation, spontaneous bleeding and mucous discharge
Fig. 3 Endoscopic findings of refractory pouchitis after rebamipide administration. Rebamipide enema has mostly healed ulcers in ileal pouch with minor scarring and no inflammatory mucosa or bleeding. However, partial lack of vascular pattern, slight edema and focal granular appearance persist in the ileal pouch
medical strategies have had limited therapeutic options [17, 18], and some have ultimately required total colectomy . Total proctocolectomy with IPAA has become the surgery of choice for the definitive management of UC because it avoids a permanent stoma while removing all diseased colonic mucosa , but it is frequently complicated by pouchitis . The exact incidence of pouchitis following IPAA is unknown, and figures vary significantly among studies (7–59%). In addition, the etiology of pouchitis is not entirely understood. Bacterial overgrowth, altered balance of luminal bacteria, mucosal ischemia, nutritional deficiencies, lack of short-chain fatty acids and fecal bile acid toxicity have all been suggested as possible etiological factors . Some authors have also suggested that pouchitis could be due to a missed diagnosis of CD or a novel third form of IBD . Our patient was diagnosed with UC and severe pouchitis based on histological findings and the JDCP. The antibiotics MNZ and CFX have often been applied as a first-line therapy for pouchitis [22, 23]. Some patients respond to this regimen, and a smaller fraction responds to conventional medications with aminosalicylates, corticosteroids and immunomodulators. However, a proportion of patients with chronic pouchitis remain
unresponsive to these therapies. Our patient did not respond to a combination of MNZ and CFX, and endoscopic findings revealed similar mucosal damage between refractory pouchitis and ulcerative colitis. Rebamipide is an effective anti-ulcer drug [14, 24] that is widely applied in Japan to treat gastric ulcers . It also potently promotes EGF activity and EGF-receptor expression , suppresses inflammation, inhibits neutrophil functions [11–13] and has a proven anti-ulcer effect in animal models . Rebamipide appears to activate a genetic program that promotes angiogenesis and signals for cell growth and tissue regeneration in gastric epithelial cells [25, 26]. Mildly to moderately active distal UC and proctitis might be treatable using rebamipide enemas . These findings suggest that rebamipide would have significant potential for treating active UC and pouchitis when delivered as a rectal enema. In conclusion, pouchitis that was refractory to conventional antibiotic and corticosteroid medication was successfully treated with rebamipide. Thus, its anti-ulcerative properties and its ability to activate epithelial cell regeneration might explain the effectiveness of rebamipide against severe pouchitis.
Clin J Gastroenterol (2009) 2:404–407
References 1. Hanauer SB. Medical therapy for ulcerative colitis 2004. Gastroenterology. 2004;126:1582–92. 2. Braveman JM, Schoetz DJ Jr, Marcello PW, Roberts PL, Coller JA, Murray JJ, et al. The fate of the ileal pouch in patients developing Crohn’s disease. Dis Colon Rectum. 2004;47:1613–9. 3. Kuisma J, Jarvinen H, Kahri A, Farkkila M. Factors associated with disease activity of pouchitis after surgery for ulcerative colitis. Scand J Gastroenterol. 2004;39:544–8. 4. Shen B, Fazio VW, Remzi FH, Lashner BA. Clinical approach to diseases of ileal pouch–anal anastomosis. Am J Gastroenterol. 2005;100:2796–807. 5. Achkar JP, Al-Haddad M, Lashner B, Remzi FH, Brzezinski A, Shen B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3:60–6. 6. Shen B, Fazio VW, Remzi FH, Brzezinski A, Bennett AE, Lopez R, et al. Risk factors for diseases of ileal pouch–anal anastomosis after restorative proctocolectomy for ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:81–9 (quiz 2-3). 7. Mann SD, Pitt J, Springall RG, Thillainayagam AV. Clostridium difficile infection—an unusual cause of refractory pouchitis: report of a case. Dis Colon Rectum. 2003;46:267–70. 8. Munoz-Juarez M, Pemberton JH, Sandborn WJ, Tremaine WJ, Dozois RR. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum. 1999;42:117–20. 9. Moonka D, Furth EE, MacDermott RP, Lichtenstein GR. Pouchitis associated with primary cytomegalovirus infection. Am J Gastroenterol. 1998;93:264–6. 10. Tarnawski A, Arakawa T, Kobayashi K. Rebamipide treatment activates epidermal growth factor and its receptor expression in normal and ulcerated gastric mucosa in rats: one mechanism for its ulcer healing action? Dig Dis Sci. 1998;43:90S–8S. 11. Aihara M, Imagawa K, Funakoshi Y, Ohmoto Y, Kikuchi M. Effects of rebamipide on production of several cytokines by human peripheral blood mononuclear cells. Dig Dis Sci. 1998;43:160S–6S. 12. Aihara M, Azuma A, Takizawa H, Tsuchimoto D, Funakoshi Y, Shindo Y, et al. Molecular analysis of suppression of interleukin8 production by rebamipide in Helicobacter pylori-stimulated gastric cancer cell lines. Dig Dis Sci. 1998;43:174S–80S. 13. Shimada S, Inoue K, Kuramoto M, Suzuki S, Yamamoto K, Ogawa M. Preoperative administration of rebamipide significantly lowers body temperature and circulating interleukin-6 in gastric cancer patients after gastrectomy. Dig Surg. 2003;20:500–5.
407 14. Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci. 1998;43:5S–13. 15. Makiyama K, Takeshima F, Hamamoto T. Efficacy of rebamipide enemas in active distal ulcerative colitis and proctitis: a prospective study report. Dig Dis Sci. 2005;50:2323–9. 16. Makiyama K, Takeshima F, Kawasaki H, Zea-Iriarte WL. Antiinflammatory effect of rebamipide enema on proctitis type ulcerative colitis: a novel therapeutic alternative. Am J Gastroenterol. 2000;95:1838–9. 17. Shanahan F. Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics. Gastroenterology. 2001;120:622–35. 18. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003;3:81–92. 19. Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121:255–60. 20. Fazio VW, Ziv Y, Church JM, Oakley JR, Lavery IC, Milsom JW, et al. Ileal pouch–anal anastomoses complications and function in 1005 patients. Ann Surg. 1995;222:120–7. 21. Pemberton JH, Kelly KA, Beart RW Jr, Dozois RR, Wolff BG, Ilstrup DM. Ileal pouch–anal anastomosis for chronic ulcerative colitis. Long-term results. Ann Surg. 1987;206:504–13. 22. Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology. 2003;124:1636–50. 23. Gionchetti P, Morselli C, Rizzello F, Romagnoli R, Campieri M, Poggioli G, et al. Management of pouch dysfunction or pouchitis with an ileoanal pouch. Best Pract Res Clin Gastroenterol. 2004;18:993–1006. 24. Genta RM. Review article: the role of rebamipide in the management of inflammatory disease of the gastrointestinal tract. Aliment Pharmacol Ther. 2003;18(Suppl 1):8–13. 25. Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K. Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine. Dig Dis Sci. 1995;40:2469–72. 26. Tarnawski AS, Chai J, Pai R, Chiou SK. Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action? Dig Dis Sci. 2004;49:202–9.