Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis

www.nature.com/scientificreports OPEN Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis Fumie Shimada 1,6, Yusuke Yoshimatsu 1,6, Tomohisa Sujino 2*, Tomohiro Fukuda 1,3, Yasuhiro Aoki 1, Yukie Hayashi 1,2, Anna Tojo 1,2, Takaaki Kawaguchi 1, Hiroki Kiyohara 1, Shinya Sugimoto 1, Kosaku Nanki 1, Yohei Mikami 1, Kentaro Miyamoto 1,4, Kaoru Takabayashi 2, Naoki Hosoe 2, Motohiko Kato 2, Haruhiko Ogata 2, Makoto Naganuma 1,5 & Takanori Kanai 1* Indigo naturalis is an effective treatment for ulcerative colitis. However, long-term use of indigo naturalis causes adverse events, such as pulmonary hypertension. The natural history of patients with ulcerative colitis who discontinued indigo naturalis after induction therapy is unknown. Moreover, the clinical features of patients who relapsed within 52 weeks after the discontinuation of indigo naturalis are unclear. This study aimed to assess the clinical outcomes of patients with ulcerative colitis after discontinuation of indigo naturalis and to identify potential markers responsible for relapse. This single-center retrospective study investigated the follow-up of 72 patients who achieved a clinical response 8 weeks after indigo naturalis treatment. We observed relapse in patients with ulcerative colitis after the discontinuation of indigo naturalis. We analyzed the factors predicting long-term outcomes after discontinuation of indigo naturalis. Relapse was observed in 24%, 57%, and 71% of patients at 8, 26, and 52 weeks, respectively. There were no predictive markers in patients who relapsed within 52 weeks after the discontinuation of indigo naturalis. The ulcerative colitis relapse rate after indigo naturalis discontinuation was high. Follow-up treatment is required after the discontinuation of indigo naturalis in patients with ulcerative colitis. Keywords Indigo naturalis, Ulcerative colitis, Relapse, Discontinuation Ulcerative colitis (UC) is a chronic inflammation of the large intestine that causes abdominal pain, diarrhea, and bloody mucous stools. UC management aims to control clinical symptoms, maintain remission, promote mucosal healing, and prevent r elapse1. Various treatments have been developed, including 5-aminosalicylic acid (5-ASA), corticosteroids2, calcineurin inhibitors3, anti-tumor necrosis factor(TNF)-α inhibitors4–7, antiIL12/23p40 inhibitors8, Janus kinase(JAK) inhibitors9–11, anti-α4β7 integrin inhibitors12, and integrin α4 inhibitors13 to achieve mucosal healing in many patients with UC. However, some patients with refractory UC eventually require colectomies. Therefore, therapies with new mechanisms of action are needed for UC treatment. Indigo naturalis (IN), made from fermented indigo herbs, has been used as an anti-inflammatory food in China since ancient times. In the 1960s, IN was used to treat UC in China, but only a few English language studies have reported its use as a t reatment14,15. The INDIGO Study published in 2018 reported a clinical response rate of 69.6% (13.6% placebo) and a clinical remission rate of 26.1% (4.5% placebo) after treatment with 0.5 g I N16. IN has been reported to be effective in patients resistant to existing therapies17. IN contains indigo and indirubin 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku‑ku, Tokyo 160‑8582, Japan. 2Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku‑ku, Tokyo 160‑8582, Japan. 3Division of Gastroenterology, Yokohama Municipal Citizen’s Hospital, 1‑1, Nishimachi, Mitsuzawa, Kanagawaku, Yokohama, Kanagawa 221‑0855, Japan. 4Miyarisan Pharmaceutical Co., Ltd., 1‑10‑3, Kaminakazato, Kita‑ku, Tokyo 114‑0016, Japan. 5Department of Gastroenterology and Hepatology, Kansai Medical University, 2‑3‑1, Shinmachi, Maikatashi, Osaka 573‑1191, Japan. 6These authors contributed equally: Fumie Shimada and Yusuke Yoshimatsu. *email: ; Scientific Reports | (2024) 14:5778 | https://doi.org/10.1038/s41598-024-56543-y 1 Vol.:(0123456789) www.nature.com/scientificreports/ that act on the aryl hydrocarbon receptor (AHR). The precise mechanism of AHR is not known, but in murine models, the AHR ligand induces IL-22, which promotes mucosal healing via innate lymphoid cells 318,19. Mouse experiments have shown that IN acts on AHR ligands in intestinal epithelial cells to initiate Treg induction; AHR signaling plays an important role in the regeneration of intestinal epithelial cells20. A recent study demonstrated that AHR signals from epithelial cells accumulate Tregs and ameliorate inflammation and epithelial d amage21. IN is categorized as a food, not a drug, under Japanese law, so it is not included in the Japanese Ulcerative Colitis Drug/Treatment Guidelines, but is available at pharmacies. IN has become the treatment of choice for ulcerative colitis in Asia, especially in Japan. Although accumulating evidence shows that IN is effective for the treatment of UC, it induces some adverse events (AEs), including pulmonary arterial hypertension (PAH), intussusception, and an increase in liver enzyme levels. An adverse event survey conducted mainly by Keio University Hospital in 2017 examined 877 patients receiving IN in 45 facilities nationwide. PAH was reversible in all patients who underwent long-term (> 8 weeks) treatment with IN; however, some required treatment. Intussusception occurred within 2 months of IN treatment, and surgery was required in 4 of the 10 cases. Of the 40 cases of elevated liver enzymes, approximately half occurred within 2 months of initiation of IN therapy, but the level improved in all patients upon IN discontinuation22. Long-term intake of IN increases the risk of AEs; therefore, the use of IN as maintenance therapy is not recommended22,23. Once induction therapy using IN was successful in treating patients with UC, it was discontinued. However, there are no real-world data on the clinical course of patients with UC after discontinuation of IN. Therefore, we aimed to assess the real-world data on the natural history of patients with UC after IN discontinuation. In addition, we analyzed potential markers in the population that sustained remission 52 weeks after discontinuation of IN. Methods Study design and patient population A single-center retrospective study design was used to investigate the follow-up of patients treated with IN between 2015 and 2020. Powdered IN (Fujian Province, China) was purchased from Uchidawakanyaku Ltd. (Tokyo, Japan). Patients on treatment with IN (0.5 or 1.0 g per day) and those who exhibited clinical response after 8 weeks of IN therapy were enrolled in this study. The IN dose was determined after a consultation with each patient (one patient used 0.5 g IN per day, other patients used 1.0 g IN per day). Patients treated with Chinese herbal medicines, including IN, in private clinics were (...truncated)