Title: Introducing Traditional Herbal Medicine into Conventional Health Care in Treating Ulcerative Colitis: Primum Non Nocere
Abstract: See "Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis," by Naganuma M, Sugimoto S, Mitsuyama K, et al, on page 935. See "Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis," by Naganuma M, Sugimoto S, Mitsuyama K, et al, on page 935. Because inflammatory bowel disease (IBD) usually shows a chronic relapsing and remitting course with medical intractability in a substantial proportion of patients, various types of alternative medicines have been tried for treating IBD. Herbal medicine or phytotherapy is one form of alternative medicine that has been practiced for centuries, particularly in traditional Chinese medicine. Complementary and alternative medicine have been reported to be used by 30% to 50% of patients with IBD.1Koning M. Ailabouni R. Gearry R.B. et al.Use and predictors of oral complementary and alternative medicine by patients with inflammatory bowel disease: a population-based, case-control study.Inflamm Bowel Dis. 2013; 19: 767-778Crossref PubMed Scopus (55) Google Scholar, 2Cheifetz A.S. Gianotti R. Luber R. et al.Complementary and alternative medicines used by patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 415-429.e15Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar To date, there have been several placebo-controlled trials that have evaluated the efficacy of alternative medicinal agents such as marijuana, curcumin, aloe vera, extracts of Andrographis paniculata, and wheat grass juice (Triticum aestivum) for patients with IBD.2Cheifetz A.S. Gianotti R. Luber R. et al.Complementary and alternative medicines used by patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 415-429.e15Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Positive results have been observed in oral curcumin,3Lang A. Salomon N. Wu J.C. et al.Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial.Clin Gastroenterol Hepatol. 2015; 13: 1444-1449.e1Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar paniculata extracts,4Sandborn W.J. Targan S.R. Byers V.S. et al.Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.Am J Gastroenterol. 2013; 108: 90-98Crossref PubMed Scopus (117) Google Scholar and wheat grass juice5Ben-Arye E. Goldin E. Wengrower D. et al.Wheat grass juice in the treatment of active distal ulcerative colitis: a randomized double-blind placebo-controlled trial.Scand J Gastroenterol. 2002; 37: 444-449Crossref PubMed Scopus (159) Google Scholar treatments for patients with active ulcerative colitis (UC; Table 1). However, most studies have small to modest sample sizes and the use of alternative strategies are still limited owing to uncertain dosing and safety issues.Table 1Herbal Preparations With Clinical Efficacy for Patients With Ulcerative Colitis in Randomized, Double-Blind, Placebo-Controlled Clinical TrialsStudyHerbal PreparationsStudy PeriodPatients and InterventionKey OutcomesAdverse EventsLang et al3Lang A. Salomon N. Wu J.C. et al.Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial.Clin Gastroenterol Hepatol. 2015; 13: 1444-1449.e1Abstract Full Text Full Text PDF PubMed Scopus (214) Google ScholarCurcuminJuly 2011–June 2014Curcumin capsule 3 g/d (n = 26) or placebo (n = 24) for 1 mo with continuous mesalamine for patients with mild to moderate ulcerative colitis (Simple Clinical Colitis Activity Index 5–11)Clinical remission at week 4: 53.8% to curcumin vs 0% to placebo (P = .01)Clinical response at week 4: 65.4% to curcumin vs 12.5% to placebo (P < .001)Endoscopic remission at week 4: 36.4% to curcumin vs 0% to placebo (P = .043)No difference of severe adverse events between the 2 groupsSandborn et al4Sandborn W.J. Targan S.R. Byers V.S. et al.Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.Am J Gastroenterol. 2013; 108: 90-98Crossref PubMed Scopus (117) Google ScholarPaniculata extracts (HMPL-004)July 2011–June 2014Paniculata extracts 1200 mg/d (n = 74) or 1800 mg/d (n = 74) or placebo (n = 75) for 8 wk for patients with mild to moderate ulcerative colitis (Mayo score 4–10)Clinical response at week 8: 44.6% to 1200 mg/d (P = .592 vs placebo); 59.5% to 1800 mg (P = .018 vs placebo); 40.0% to placeboMucosal healing: 37.8% to 1200 mg/d (P = .582 vs placebo); 50.0% to 1800 mg (P = .040 vs placebo); 33.3% to placeboAny adverse event, adverse events leading to study drug discontinuation, and serious adverse events were not different among groupsBen-Arye et al5Ben-Arye E. Goldin E. Wengrower D. et al.Wheat grass juice in the treatment of active distal ulcerative colitis: a randomized double-blind placebo-controlled trial.Scand J Gastroenterol. 2002; 37: 444-449Crossref PubMed Scopus (159) Google ScholarWheat grass juiceNot availableWheat grass juice 100 mL/d (n = 11) or placebo (n = 12) for 1 mo for patients with active ulcerative colitis involving left colonDisease activity index score improvement: 90.9% to wheat grass juice vs 41.7% to placebo (P = .031)Sigmoidoscopic improvement: 77.8% to wheat grass juice vs 30% to placebo (P = .127)Nausea in wheat grass juice group (33.3%)No adverse events in placebo groupNaganuma et al6Naganuma 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: 935-947Abstract Full Text Full Text PDF PubMed Scopus (96) Google ScholarIndigo naturalisMarch 2016–December 2016Indigo naturalis 0.5 g/d (n = 23), 1.0 g/d (n = 20), or 2.0 g/d (n = 21), or placebo (n = 22) for 8 wk for patients with active ulcerative colitis with Mayo scores ≥6Clinical response at 8 wk: 69.6% to 0.5 g/d (P = .0002 vs placebo); 75.0% to 1.0 g/d (P = .0001 vs placebo); 81.0% to 2.0 g/d (P < .0001 vs placebo); 13.6% to placebo (Cochran-Armitage trend test P < .0001 vs placebo)Mucosal healing at 8 wk: 56.5% to 0.5 g/d (P = .0045 vs placebo); 60.0% to 1.0 g/d (P = .0032 vs placebo); 47.6% to 2.0 g/d (P = .0217 vs placebo): 13.6% to placebo (Cochran-Armitage trend test P = .0278)Early termination of the trial owing to a report of a pulmonary arterial hypertension in a patient who used self-purchased indigo naturalis 2 g/d for 6 moMildly increased transaminase levels in 10 patients in the indigo naturalis group (15.6%) and in 2 patients in the placebo group (9.1%) Open table in a new tab Indigo naturalis (also referred to as Qing-Dai) is an herbal preparation extracted from leaves and stems of Baphicacanthus cusia (Nees) Bremek that has been used as a blue dye since ancient times.6Naganuma 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: 935-947Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 7Lin Y.K. Wong W.R. Chang Y.C. et al.The efficacy and safety of topically applied indigo naturalis ointment in patients with plaque-type psoriasis.Dermatology. 2007; 214: 155-161Crossref PubMed Scopus (61) Google Scholar Indigo naturalis has also been used as an antipyretic, an antiphlogistic, and as a hemostatic remedy for centuries in traditional Chinese medicine.8Stasiak N. Kukula-Koch W. Glowniak K. Modern industrial and pharmacological applications of indigo dye and its derivatives–a review.Acta Pol Pharm. 2014; 71: 215-221PubMed Google Scholar, 9Suzuki H. Kaneko T. Mizokami Y. et al.Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.World J Gastroenterol. 2013; 19: 2718-2722Crossref PubMed Scopus (51) Google Scholar For specific diseases, it was reported to be efficacious for psoriasis7Lin Y.K. Wong W.R. Chang Y.C. et al.The efficacy and safety of topically applied indigo naturalis ointment in patients with plaque-type psoriasis.Dermatology. 2007; 214: 155-161Crossref PubMed Scopus (61) Google Scholar, 10Yuan Z.Z. Yuan X. Xu Z.X. Studies on tabellae indigo naturalis in treatment of psoriasis.J Tradit Chin Med. 1982; 2: 306PubMed Google Scholar, 11Lin Y.K. Chang C.J. Chang Y.C. et al.Clinical assessment of patients with recalcitrant psoriasis in a randomized, observer-blind, vehicle-controlled trial using indigo naturalis.Arch Dermatol. 2008; 144: 1457-1464Crossref PubMed Scopus (79) Google Scholar, 12Lin Y. See L. Huang Y. et al.Comparison of refined and crude indigo naturalis ointment in treating psoriasis: randomized, observer-blind, controlled, intrapatient trial.Arch Dermatol. 2012; 148: 397-400Crossref PubMed Scopus (30) Google Scholar and chronic hemorrhagic radiation proctitis13Yuan G. Ke Q. Su X. et al.Qing Dai, a traditional Chinese medicine for the treatment of chronic hemorrhagic radiation proctitis.Chin-Ger J Clin Oncol. 2009; 8: 114Crossref Google Scholar in studies from China and Taiwan. For the treatment of IBD, a previous retrospective case series of 9 patients9Suzuki H. Kaneko T. Mizokami Y. et al.Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.World J Gastroenterol. 2013; 19: 2718-2722Crossref PubMed Scopus (51) Google Scholar and an open-label, prospective pilot study of 20 patients14Sugimoto 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: 193-201Crossref PubMed Scopus (61) Google Scholar suggested the efficacy of oral indigo naturalis for inducing remission in active UC. Based on those encouraging results, in this issue of Gastroenterology, Naganuma et al6Naganuma 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: 935-947Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar reported results from the first randomized, controlled trial to investigate the safety and efficacy of indigo naturalis in patients with moderate to severe UC. In this study, a total of 86 subjects were randomly assigned to groups given a daily dose of 0.5, 1.0, or 2.0 g indigo naturalis or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was clinical response at week 8 and secondary endpoints included clinical remission, endoscopic remission, and levels of quantitative fecal blood test and fecal calprotectin at week 8. However, the trial was early terminated owing to an external reason: the report of a possible adverse event of pulmonary arterial hypertension (PAH) in a patient with UC who used self-purchased indigo naturalis 2 g/d for 6 months.15Nishio M. Hirooka K. Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension.Eur Heart J. 2016; 37: 1992Crossref PubMed Scopus (28) Google Scholar In the intention-to-treat analysis, a significant, dose-dependent linear trend was observed in proportions of patients with clinical responses (13.6% to placebo [3 of 22]; 69.6% to 0.5 g indigo naturalis [16 of 23]; 75.0% to 1.0 g indigo naturalis [15 of 20]; and 81.0% to 2.0 g indigo naturalis [17 of 21]) (Cochran-Armitage trend test P < .0001 compared with placebo). Clinical remission rates at week 8 were also significantly higher in the 1.0 g indigo naturalis group (55.0%; P = .0004) and the 2.0 g indigo naturalis group (38.1%; P = .0093) than in the placebo group (4.5%). Mucosal healing rates were 13.6% (3 of 22) in the placebo group, 56.5% (13 of 23) in the 0.5 g indigo naturalis group, 60.0% (12 of 20) in the 1.0 g indigo naturalis group, and 47.6% (10 of 21) in the 2.0 g indigo naturalis group (Cochran-Armitage trend test P = .0278 compared with placebo). Moreover, a quantitative fecal immunochemical blood test and a fecal calprotectin test also revealed better outcomes in groups treated with indigo naturalis than placebo. In terms of safety, all 3 groups treated with indigo naturalis had a significantly increased mean transaminase levels during ≥1 visit over the trial period; a similar increase was not observed in the placebo group. The abnormalities in the 10 patients in the indigo naturalis group recovered during the study without a dose reduction (n = 6) or after completion of the study (n = 4). Although this study demonstrated the potential for indigo naturalis in inducing clinical response, mucosal healing, and biochemical response in patients with moderate to severe UC, its mechanism of action remains unclear. In a recent study by Kawai et al,16Kawai S. Iijima H. Shinzaki S. et al.Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation.J Gastroenterol. 2017; 52: 904-919Crossref PubMed Scopus (61) Google Scholar indigo naturalis improved murine dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor activation, but more mechanistic studies are needed. In addition, standardized production protocols are needed to provide consistent quality before its use as conventional therapy. Furthermore, a report of PAH foster safety concerns.15Nishio M. Hirooka K. Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension.Eur Heart J. 2016; 37: 1992Crossref PubMed Scopus (28) Google Scholar In this trial, no cases of PAH were reported during 8 weeks of treatment and 16 months of total follow-up after study termination.6Naganuma 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: 935-947Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar PAH also did not develop in any patient who used indigo naturalis for up to 4 months in previous 2 studies.9Suzuki H. Kaneko T. Mizokami Y. et al.Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.World J Gastroenterol. 2013; 19: 2718-2722Crossref PubMed Scopus (51) Google Scholar, 14Sugimoto 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: 193-201Crossref PubMed Scopus (61) Google Scholar However, follow-up periods were too short to assess the risk of PAH associated with indigo naturalis. Similarly, mild liver test abnormalities developed in 10 out 64 patients in the indigo naturalis-treated groups (15.6%), even in the low-dose group (0.5 g/d).6Naganuma 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: 935-947Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Together with a case report of acute hepatitis associated with Fu Fang Qing Dai Wan, a Chinese herbal preparation including indigo naturalis,17Verucchi G. Calza L. Attard L. et al.Acute hepatitis induced by traditional Chinese herbs used in the treatment of psoriasis.J Gastroenterol Hepatol. 2002; 17: 1342-1343Crossref PubMed Scopus (20) Google Scholar the hepatotoxicity of indigo naturalis is an issue yet to be resolved as well. Greater numbers of patients and longer term follow-up are needed to adequately assess its long-term safety profile. In "real life," indigo naturalis is currently selected by a substantial number of patients with UC as an alternative therapy in East Asian countries including China, Japan, and Korea, without safety monitoring by health care authorities in many areas. Therefore, in daily clinical practice, IBD patients taking indigo naturalis should be closely monitored and evaluated by their gastroenterologists and IBD specialists. In summary, based on the canonical primum non nocere (first, do no harm) medical concern, despite its potential as an anti-inflammatory drug, indigo naturalis should not be recommended because of serious adverse events, including PAH. Safety of indigo naturalis should be proved in animal experiments before further human studies. Moreover, various types of alternative therapy based on traditional herbal medicine are warranted to be strictly evaluated in terms of safety concerns. Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative ColitisGastroenterologyVol. 154Issue 4PreviewIndigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. Full-Text PDF