Advertisement

Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study

  • Makoto NaganumaEmail author
  • Shinya Sugimoto
  • Tomohiro Fukuda
  • Keiichi Mitsuyama
  • Taku Kobayashi
  • Naoki Yoshimura
  • Hidehisa Ohi
  • Shinji Tanaka
  • Akira Andoh
  • Naoki Ohmiya
  • Keiichiro Saigusa
  • Takayuki Yamamoto
  • Yuichi Morohoshi
  • Hitoshi Ichikawa
  • Katsuyoshi Matsuoka
  • Tadakazu Hisamatsu
  • Kenji Watanabe
  • Shinta Mizuno
  • Takayuki Abe
  • Yasuo Suzuki
  • Takanori Kanai
  • for the INDIGO Study Group
Original Article—Alimentary Tract

Abstract

Background

We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness.

Methods

In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5–2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8.

Results

The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8.

Conclusions

In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

Keywords

Ulcerative colitis Indigo naturalis Anti-TNFa treatment Steroid dependent 

Abbreviations

AE

Adverse event

AhR

Aryl hydrocarbon receptor

CRP

C-reactive protein

CR

Clinical response

FCP

Fecal calprotectin

FIT

Fecal immunochemical blood test

IN

Indigo naturalis

IQR

Interquartile range

ITT

Intention-to-treat

MES

Mayo endoscopic score

MH

Mucosal healing

MTWSI

Modified Truelove and Witts Severity Index

PAH

Pulmonary arterial hypertension

RCT

Randomized controlled trial

UC

Ulcerative colitis

Notes

Acknowledgements

This study was supported in part by grants from the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (to M. Naganuma). We would like to thank Editage (www.editage.jp) for English language editing.

INDIGO study group: Members in the INDIGO Study Group are Makoto Naganuma, Shinya Sugimoto, Shinta Mizuno, Yoshihiro Nakazato, Tomohiro Fukuda, Toshiaki Teratani, Haruhiko Ogata, Yasushi Iwao, Takanori Kanai (Keio University School of Medicine), Hiroshi Yamasaki, Keiichi Mitsuyama (Kurume University School of Medicine), Taku Kobayashi, Takahiko Toyonaga, Masaru Nakano, Toshifumi Hibi (Kitasato Institute Hospital), Naoki Yoshimura (Yamate Medical Center), Yoichi Sameshima, Hidehisa Ohi (Imamura hospital), Ryohei Hayashi, Yoshitaka Ueno, Shinji Tanaka (Hiroshima University Hospital), Shigeki Bamba, Akira Andoh (Shiga University of Medical Science), Mamoru Watanabe (Tokyo Medical and Dental University), Keiichiro Saigusa, Atsushi Nakazawa (Tokyo Saiseikai Central Hospital), Yuichi Morohoshi, Yuji Koike (Yokohama Municipal Citizen’s Hospital), Jin Imai, Hitoshi Ichikawa (Tokai University Hachioji Hospital), Takahiro Shimoyama, Takayuki Yamamoto (Yokkaichi Hazu Medical Center), Katsuyoshi Matsuoka, Ken Takeuchi, Yasuo Suzuki (Toho University Sakura Medical Center), Mitsuo Nagasaka, Naoki Ohmiya (Fujita Health University School of Medicine), Atsuo Kitano (Wakakusa Daiichi Hospital), Shinya Ashizuka, Haruhiko Inatsu (University of Miyazaki), Kei Onodera, Hiroshi Nakase (Sapporo Medical University School of Medicine), Kazuya Kitamura (Kanazawa University Hospital), Kentaro Ikeya, Hiroyuki Hanai (Hamamatsu South Hospital), Chikako Watanabe, Ryota Hokari (National Defense Medical College), Fumihito Hirai (Fukuoka University Chikushi Hospital), Yuji Naito (Kyoto prefecture University), Namiko Hoshi (Kobe University), Fukunori Kinjo (Urazoe General Hospical), Yo Ishiguro (Hirosaki National Hospital), Makoto Sasaki (Aichi Medical University), Takayuki Matsumoto (Iwate Medical University), Kenji Watanabe (Hyogo College of Medicine), Tadakazu Hisamatsu (Kyorin University School of Medicine), Fumiya Sano, Rachel Roberts, Takayuki Abe (Keio University), Wataru Suda (The University of Tokyo) and Masahira Hattori (Waseda University), Shinji Fukuda, and Akiyoshi Hirayama (Institute for Advanced Biosciences, Keio University).

Author contributions

MN and TKa conceived the study. MN designed the main concept of this study. MN, SS, TKo, KM, and KW drafted the main protocol. TA participated in the statistical analysis. All authors participated in patient enrolment and clinical data acquisition. MN and SS drafted and wrote the manuscript. All authors contributed to critical review and approved the final draft.

Funding

This study was funded by Keio Fukuzawa Memorial Fund.

Compliance with ethical standards

Conflict of interest

Makoto Naganuma received commercial research funding from EA Pharma Co., Ltd. and Mochida Pharmaceutical Co., Ltd., outside the submitted work. Taku Kobayashi received advisory fee from Alfresa Pharma, Covidien, Eli Lilly Japan K.K, Ferring Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Thermo Fisher Scientific Inc. and received lecture fees from Mitsubishi Tanabe Pharma Corp., AbbVie GK, Kyorin Pharmaceutical Co., Ltd., Pfizer Japan Inc., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd. Zeria Pharmaceutical Co., Ltd., Astellas Pharma Inc., Mochida Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Asahi Kasei Medical Co., Ltd., Alfresa Pharma, Ezai Pharmaceutical Co., Ltd., Gilead, Janssen Pharmaceutical K.K., and received commercial research funding from EA Pharma Co., Ltd., Thermo Fisher Scientific Inc., Alfresa Pharma, Asahi Kasei Medical Co., Ltd. Nippon Kayaku Co., outside the submitted work. Naoki Yoshimura received lecture fees from Mitsubishi Tanabe Pharma Corp., AbbVie GK, and Mochida Pharmaceutical Co., Ltd., outside the submitted work. Naoki Omiya received lecture fees from Mylan EPD and commercial research funding from Mylan EPD, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K, Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., outside the submitted work. Yasuo Suzuki received lecture fees from Mitsubishi Tanabe Pharma Corp., Mochida Pharmaceutical Co., Ltd., AbbVie GK, Zeria Pharmaceutical co., Ltd., Kyorin Pharmaceutical Co., Ltd. Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., EA Pharma Co., Ltd. and research grants from Mitsubishi Tanabe Pharma Corp. and AbbVie GK, EA Pharma Co., Ltd. Kissei Pharma Co., Ltd., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., outside the submitted work. Tadakazu Hisamatsu received lecture fees from AbbVie GK, EA pharma Co., Ltd., Eisai Co., Ltd., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corp., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd. Mochida Pharmaceutical Co., Ltd., and research grants from AbbVie GK, Asahi Kasei Medical Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd, Mochida Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd., outside the submitted work. Takanori Kanai received lecture fees from Mitsubishi Tanabe Pharma Corp, Astellas Pharma Inc, Miyarisan Pharmaceutical Co., Ltd. AstraZeneca Plc, EA Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., grants from AbbVie GK, Mochida Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corp, Takeda Pharmaceutical Co., Ltd., Nihon Kayaku, Yakult Honsha Co., Ltd., Zeria Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Ezaki Glico Co., Ltd. JIMRO Co., Ltd., EN Otsuka Pharmaceutical Co., Ltd., outside the submitted work. All other authors have no competing interests to declare.

References

  1. 1.
    Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet. 2017;389:1756–70.CrossRefPubMedGoogle Scholar
  2. 2.
    Arai M, Naganuma M, Sugimoto S, et al. The ulcerative colitis endoscopic index of severity is useful to predict medium- to long-term prognosis in ulcerative colitis patients with clinical remission. J Crohns Colitis. 2016;10:1303–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133:412–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Naganuma M, Mizuno S, Nanki K, et al. Recent trends and future directions for the medical treatment of ulcerative colitis. Clin J Gastroenterol. 2016;9:329–36.CrossRefPubMedGoogle Scholar
  5. 5.
    Zelante T, Iannitti RG, Cunha C, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Qiu J, Guo X, Chen ZM, et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity. 2013;39:386–99.CrossRefPubMedGoogle Scholar
  7. 7.
    Sugimoto S, Naganuma M, Kanai T. Indole compounds may be promising medicines for ulcerative colitis. J Gastroenterol. 2016;51:853–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357:6349.CrossRefGoogle Scholar
  9. 9.
    Sugimoto S, Naganuma M, Kiyohara H, et al. Clinical efficacy and safety of oral qing-dai in patients with ulcerative colitis: a single-center open-label prospective study. Digestion. 2016;93:193–201.CrossRefPubMedGoogle Scholar
  10. 10.
    Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22:598–605.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology. 2018;154:935–47.CrossRefPubMedGoogle Scholar
  12. 12.
    Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J. 2016;37:1992.CrossRefPubMedGoogle Scholar
  13. 13.
    Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Dignass A, Eliakim R, Magro F, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012;6:965–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Nakarai A, Kato J, Hiraoka S, et al. Evaluation of mucosal healing of ulcerative colitis by a quantitative fecal immunochemical test. Am J Gastroenterol. 2013;108:83–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Gisbert JP, Linares PM, McNicholl AG, et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther. 2009;30:126–37.CrossRefPubMedGoogle Scholar
  18. 18.
    Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMedGoogle Scholar
  19. 19.
    Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–65.CrossRefPubMedGoogle Scholar
  20. 20.
    Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:96–109.CrossRefPubMedGoogle Scholar
  22. 22.
    Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710.CrossRefPubMedGoogle Scholar
  23. 23.
    Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723–36.CrossRefPubMedGoogle Scholar
  24. 24.
    Amiot A, Grimaud JC, Peyrin-Biroulet L, et al. Effectiveness and safety of vedolizumab induction therapy for patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2016;14:1593–601.CrossRefPubMedGoogle Scholar
  25. 25.
    Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118:534–44.PubMedPubMedCentralGoogle Scholar
  26. 26.
    D’Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2218–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Costa F, Mumolo MG, Ceccarelli L, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut. 2005;54:364–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Naganuma M, Sugimoto S, Suzuki H, et al. Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey. J Gastroenterol. 2019.  https://doi.org/10.1007/s00535-019-01591-9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  • Makoto Naganuma
    • 1
    Email author
  • Shinya Sugimoto
    • 1
  • Tomohiro Fukuda
    • 1
  • Keiichi Mitsuyama
    • 2
  • Taku Kobayashi
    • 3
  • Naoki Yoshimura
    • 4
  • Hidehisa Ohi
    • 5
  • Shinji Tanaka
    • 6
  • Akira Andoh
    • 7
  • Naoki Ohmiya
    • 8
  • Keiichiro Saigusa
    • 9
  • Takayuki Yamamoto
    • 10
  • Yuichi Morohoshi
    • 11
  • Hitoshi Ichikawa
    • 12
  • Katsuyoshi Matsuoka
    • 13
    • 14
  • Tadakazu Hisamatsu
    • 15
  • Kenji Watanabe
    • 16
  • Shinta Mizuno
    • 1
  • Takayuki Abe
    • 17
  • Yasuo Suzuki
    • 18
  • Takanori Kanai
    • 1
  • for the INDIGO Study Group
  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of MedicineTokyoJapan
  2. 2.Division of Gastroenterology, Department of MedicineKurume University School of MedicineKurumeJapan
  3. 3.Center for Advanced IBD Research and TreatmentKitasato University Kitasato Institute HospitalTokyoJapan
  4. 4.Department of Internal Medicine, Division of IBDTokyo Yamate Medical CenterTokyoJapan
  5. 5.Department of GastroenterologyImamura HospitalKagoshimaJapan
  6. 6.Department of Endoscopy and MedicineHiroshima University HospitalHiroshimaJapan
  7. 7.Department of MedicineShiga University of Medical ScienceOtsuJapan
  8. 8.Department of GastroenterologyFujita Health University School of MedicineToyoakeJapan
  9. 9.Department of MedicineTokyo Saiseikai Central HospitalTokyoJapan
  10. 10.IBD CenterYokkaichi Hazu Medical CenterYokkaichiJapan
  11. 11.Department of MedicineYokohama Municipal Citizen’s HospitalYokohamaJapan
  12. 12.Department of GastroenterologyTokai University Hachioji HospitalHachiojiJapan
  13. 13.Department of GastroenterologyToho University Sakura Medical CenterSakuraJapan
  14. 14.Department of Internal MedicineToho University Sakura Medical CenterSakuraJapan
  15. 15.The Third Department of Internal MedicineKyorin University School of MedicineMitakaJapan
  16. 16.Department of Intestinal Inflammation ResearchHyogo College of MedicineNishinomiyaJapan
  17. 17.Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical and Translational Research CenterKeio University School of MedicineTokyoJapan
  18. 18.Inflammatory Bowel Disease CenterToho University Sakura Medical CenterSakuraJapan

Personalised recommendations