This study aimed to evaluate risk factors for resistance to proton-pump inhibitor (PPI) therapy among patients with reflux esophagitis (RE) and nonerosive reflux disease (NERD) in gastroesophageal reflux disease (GERD) using a standardized questionnaire in Japan: the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG).
One hundred fifty-eight patients who underwent upper gastrointestinal endoscopy were enrolled: 87 were diagnosed with RE (mean age: 59.5 ± 15.1 years; male/female: 47/39) and 71 with NERD (mean age 53.0 ± 17.6 years; male/female 22/49). The patients were divided into two groups according to improvement after PPI treatment evaluated by FSSG: rapid responders were patients with ≥50 % improvement according to FSSG, and low responders were those with <50 % improvement according to FSSG. All patients were treated with the PPI rabeprazole (10 mg/day) for 4 weeks.
Response rate to PPI therapy was 65.5 % (57/87) in RE and 54.9 % (39/71) in NERD, indicating that the PPI treatment was more effective for RE. In RE, risk factors for PPI resistance indicated by univariate analysis were low stature and high body mass index. Low stature was a risk factor in multivariate analysis. With regard to NERD, univariate analysis indicated that female gender, high stature, low body weight, and low total FSSG score were risk factors for PPI resistance. Low FSSG score was a risk factor in multivariate analysis.
By the present study, we identified the risk factors for PPI resistance in RE and GERD using FSSG.
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Fass R. Epidemiology and pathophysiology of symptomatic gastroesophageal reflux disease. Am J Gastroenterol. 2003;98:S2–7.
Vakil N. van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.
Kawagichi H, Haruma K, Komoto K, Yoshihara M, Sumii K, Kajiyama G. Helicobacter pylori infection is the major risk factor for atrophic gastritis. Am J Gastroenterol. 1996;91:959–62.
Watanabe A, Iwakiri R, Yamaguchi D, Higuchi T, Tsuruoka N, Miyahara K, Akutagawa K, Sakata Y, Fujise T, Oda Y, Shimoda R, Sakata H, Fujimoto K. Risk factors for resistance to proton pump inhibitor maintenance therapy for reflux esophagitis in Japanese women over 60 years. Digestion. 2012;86:323–8.
Fujimoto K. Prevalence and epidemiology of gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther. 2004;20:5–8.
Fujiwara Y, Higuchi K, Shiba M, Yamamori K, Watanabe Y, Sasaki E, Tominaga K, Watanabe T, Oshitani N, Arakawa T. Differences in clinical characteristics between patients with endoscopy-negative reflux disease and erosive esophagitis in Japan. Am J Gastroenterol. 2005;100:754–8.
Fujimoto K, Hongo M, Maintenance Study Group. Safety and efficacy of long-term maintenance therapy with oral dose of rabeprazole 10 mg once daily in Japanese patients with reflux esophagitis. Intern Med. 2011;50:179–88.
Furukawa N, Iwakiri R, Koyama T, Okamoto K, Yoshida T, Kashiwagi Y, Ohyama T, Noda T, Sakata H, Fujimoto K. Proportion of reflux esophagitis in 6010 Japanese adults: prospective evaluation by endoscopy. J Gastroenterol. 1999;34:441–4.
Hongo M, Miwa H, Kusano M, J-FAST Group. Effect of rabeprazole treatment on health-related quality of life and symptoms in patients with reflux esophagitis: a prospective multicenter observational study in Japan. J Gastroenterol. 2011;46:297–304.
Nagahara A, Hojo M, Asaoka D, Watanabe S. Maintenance therapy of gastroesophageal reflux disease. Clin J Gastroenterol. 2010;3:61–8.
Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology. 1997;112:1798–810.
Fujimoto K, Hongo M, Maintenance Study Group. Risk factors for relapse of erosive GERD during long-term maintenance treatment with proton pump inhibitor: a prospective multicenter study in Japan. J Gastroenterol. 2010;45:1193–200.
Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol. 2009;44:518–34.
Cicala M, Emerenziani S, Guarino MP, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol. 2013;19:6529–35.
Kinoshita Y, Ishihara S. Causes of, and therapeutic approaches for, proton pump inhibitor-resistant gastroesophageal reflux disease in Asia. Therap Adv Gastroenterol. 2008;1:191–9.
Carlsson R, Dent J, Bolling-Sternevald E, Johnsson F, Junghard O, Lauritsen K, Riley S, Lundell L. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol. 1998;33:1023–9.
Kusano M, Shimoyama Y, Sugimoto S, Kawamura O, Maeda M, Minashi K, Kuribayashi S, Higuchi T, Zai H, Ino K, Horikoshi T, Sugiyama T, Toki M, Ohwada T, Mori M. Development and evaluation of FSSG: Frequency Scale for the Symptoms of GERD. J Gastroenterol. 2004;39:888–91.
Svedlund J, Sjödin I, Dotevall G. GSRS—a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1998;33:129–34.
Bai Y, Du Y, Zou D, Jin Z, Zhan X, Li ZS, Yang Y, Liu Y, Zhang S, Qian J, Zhou L, Hao J, Chen D, Fang D, Fan D, Sha W, Nie Y, Zhang X, Xu H, Lv N, Jiang B, Zou X, Fang J, Fan J, Li Y, Chen W, Wang B, Zou Y, Li Y, Sun M, Chen Q, Chen M, Zhao X, Chinese GerdQ Research Group. Gastroesophageal reflux disease questionnaire (GerdQ) in real-world practice: a national multicenter survey on 8065 patients. J Gastroenterol Hepatol. 2013;28:626–31.
Danjo A, Yamaguchi K, Fujimoto K, Saitoh T, Inamori M, Masahiko Inamori, Ando T, Shimatani T, Adachi K, Kinjo F, Kuribayashi S, Mitsufuji S, Fujiwara Y, Koyama S, Akiyama J, Takagi A, Manabe N, Miwa H, Shimoyama Y, Kusano M. Comparison of endoscopic findings with symptom assessment systems (FSSG and QUEST) for gastroesophageal reflux disease in Japanese centres. J Gastroenterol Hepatol. 2009;24:633–8.
Komatsu-Tanaka M, Iwakiri R, Fujimoto K, Fujiwara Y, Inamori M, Tanaka J, Shimatani T, Akiyama J, Ando T, Manabe N, Kinjo F, Deguchi R, Kusano M. Clinical symptoms of FSSG in gastroesophageal reflux disease are critical for PPI treatment: Japanese multi-centers with 185 patients. Dig Endosc. 2012;24:407–11.
Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo M, Richter JE, Spechler SJ, Tytgat GN, Wallin L. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–80.
Cloud ML, Enas N, Humphries TJ, Bassion S. Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). The Rabeprazole Study Group. Dig Dis Sci. 1998;43:993–1000.
Robinson M, Fitzgerald S, Hegedus R, Murthy A, Jokubaitis L, FAST Trial Investigators. Onset of symptom relief with rabeprazole: a community-based, open-label assessment of patients with erosive oesophagitis. Aliment Pharmacol Ther. 2002;16:445–54.
Miner P Jr, Orr W, Filippone J, Jokubaitis L, Sloan S. Rabeprazole in nonerosive gastroesophageal reflux disease: a randomized placebo-controlled trial. Am J Gastroenterol. 2002;97:1332–9.
Kinoshita Y, Hongo M, Japan TWICE, Study Group. Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory once-daily administration of PPI: the Japan-based TWICE study. Am J Gastroenterol. 2012;107:522–30.
Minatsuki C, Yamamichi N, Shimamoto T, Kakimoto H, Takahashi Y, Fujishiro M, Sakaguchi Y, Nakayama C, Konno-Shimizu M, Matsuda R, Mochizuki S, Asada-Hirayama I, Tsuji Y, Kodashima S, Ono S, Niimi K, Mitsushima T, Koike K. Background factors of reflux esophagitis and non-erosive reflux disease: a cross-sectional study of 10,837 subjects in Japan. PLoS One. 2013;8:e69891.
Hiyama T, Matsuo K, Urabe Y, Fukuhara T, Tanaka S, Yoshihara M, Haruma K, Chayama K. Meta-analysis used to identify factors associated with the effectiveness of proton pump inhibitors against non-erosive reflux disease. J Gastroenterol Hepatol. 2009;24:1326–32.
Sugimoto M, Nishino M, Kodaira C, Yamade M, Uotani T, Ikuma M, Umemura K, Furuta T. Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy. World J Gastroenterol. 2011;17:1858–65.
Jo SY, Kim N, Lim JH, Shin CM, Park YS, Lee DH, Jung HC. Comparison of gastroesophageal reflux disease symptoms and proton pump inhibitor response using gastroesophageal reflux disease impact scale questionnaire. J Neurogastroenterol Motil. 2013;19:61–9.
Mishima I, Adachi K, Arima N, Amano K, Takashima T, Moritani M, Furuta K, Kinoshita Y. Prevalence of endoscopically negative and positive gastroesophageal reflux disease in the Japanese. Scand J Gastroenterol. 2005;40:1005–9.
Kim N, Lee SW, Kim JI, Baik GH, Kim SJ, Seo GS, Oh HJ, Kim SW, Jeong H, Hong SJ, Shim KN, Shin JE, Park SJ, Im EH, Park JJ, Cho SI, Jung HC, H. pylori and GERD Study Group of Korean College of Helicobacter and Upper Gastrointestinal Research. Effect of Helicobacter pylori eradication on the development of reflux esophagitis and gastroesophageal reflux symptoms: a nationwide multi-center prospective study. Gut Liver. 2011;5:437–46.
Miyamoto M, Manabe N, Haruma K. Efficacy of the addition of prokinetics for proton pump inhibitor (PPI) resistant non-erosive reflux disease (NERD) patients: significance of frequency scale for the symptom of GERD (FSSG) on decision of treatment strategy. Inter Med. 2010;49:1469–76.
Saitoh T, Otsuka H, Kawasaki T, Endo H, Iga D, Tomimatsu M, Fukushima Y, Katsube T, Ogawa K, Otsuka K. Influences of CYP2C19 polymorphism on recurrence of reflux esophagitis during proton pump inhibitor maintenance therapy. Hepatogastroenterology. 2009;56:703–6.
Ohkusa T, Maekawa T, Arakawa T, Nakajima M, Fujimoto K, Hoshino E, Mitachi Y, Hamada S, Mine T, Kawahara Y, Nagai T, Aoyama N, Yoshida N, Tadokoro K, Chida N, Konda Y, Seno H, Shimatani T, Inoue M, Sato N. Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis. Aliment Pharmacol Ther. 2005;21:1331–9.
El-Serag HB. Epidemiology of non-erosive reflux disease. Digestion. 2008;78:6–10.
Furuta T, Shimatani T, Sugimoto M, Ishihara S, Fujiwara Y, Kusano M, Koike T, Hongo M, Chiba T, Kinoshita Y, Acid-Related Symptom Research Group. Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan. J Gastroenterol. 2011;46:1273–83.
Kusano M, Shimoyama Y, Kawamura O, Maeda M, Kuribayashi S, Nagoshi A, Zai H, Moki F, Horikoshi T, Toki M, Sugimoto S, Mori M. Proton pump inhibitors improve acid-related dyspepsia in gastroesophageal reflux disease patients. Dig Dis Sci. 2007;52:1673–7.
Iwakiri R, Tominaga K, Furuta K, Inamori M, Furuta T, Masuyama H, Kanke K, Nagahara A, Haruma K, Kinoshita Y, Higuchi K, Takahashi S, Kusano M, Iwakiri K, Kato M, Hongo M, Hiraishi H, Watanabe S, Miwa H, Naito Y, Fujimoto K, Arakawa T. Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan. Aliment Pharmacol Ther. 2013;38:729–40.
Sakurai K, Nagahara A, Inoue K, Akiyama J, Mabe K, Katsuhiro Mabe, Suzuki J, Habu Y, Araki A, Suzuki T, Satoh K, Nagami H, Harada R, Tano N, Kusaka M, Fujioka Y, Fujimura T, Shigeto N, Oumi T, Miwa J, Miwa H, Fujimoto K, Kinoshita Y, Haruma K. Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J-FOCUS). BMC Gastroenterol. 2012;12:42.
Tominaga K, Iwakiri R, Fujimoto K, Fujiwara Y, Tanaka M, Shimoyama Y, Umegaki E, Higuchi K, Kusano M, Arakawa T, GERD 4 Study Group. Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan. J Gastroenterol. 2012;47:284–92.
Tominaga K, Kato M, Takeda H, Shimoyama Y, Umegaki E, Iwakiri R, Furuta K, Sakurai K, Odaka T, Kusunoki H, Nagahara A, Iwakiri K, Furuta T, Murakami K, Miwa H, Kinoshita Y, Haruma K, Takahashi S, Watanabe S, Higuchi K, Kusano M, Fujimoto K, Arakawa T, G-PRIDE Study Group. A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study. J Gastroenterol. 2014;49:1392–405.
This study was partly supported by Eisai Co., Tokyo, Japan.
Written informed consent was obtained from all patients before study entry. The study was conducted in accordance with the Helsinki Declaration of the World Medical Association under the approval of the Ethics Committee in each institute.
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Akutagawa, K., Iwakiri, R., Hara, M. et al. Risk factors for low response to proton-pump inhibitor treatment in reflux esophagitis and non-erosive reflux disease evaluated by the frequency scale for the symptoms of gastroesophageal reflux disease. Esophagus 12, 225–232 (2015). https://doi.org/10.1007/s10388-014-0477-x