Skip Navigation
Skip to contents

Intest Res : Intestinal Research

Search
Advanced Search
IMPACT FACTOR
mobile search button mobile menu button

Articles

Page Path
HOME > Intest Res > Volume 17(1); 2019 > Article
Review Article Current new challenges in the management of ulcerative colitis
Tomohiro Fukudaorcid, Makoto Naganuma, Takanori Kanai,orcid
Intestinal Research 2019;17(1):36-44.
DOI: https://doi.org/10.5217/ir.2018.00126
Published online: January 25, 2019

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Correspondence to Takanori Kanai, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel: +81-3-5843-7090, Fax: +81-3-5843-7091, E-mail: takagast@z2.keio.jp
• Received: September 11, 2018   • Revised: October 5, 2018   • Accepted: October 12, 2018

© Copyright 2019. Korean Association for the Study of Intestinal Diseases. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next
  • 9,401 Views
  • 437 Download
  • 45 Web of Science
  • 45 Crossref
  • 44 Scopus
Full Article

Download PDF Download PDF

  • Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal tract. Although the cause of UC is postulated to be multifactorial in nature, including genetic predisposition, epithelial barrier defects, dysregulation of immune responses, and environmental factors, the specific pathogenesis of UC is still incompletely understood. In the treatment of UC so far, a method of suppressing immunity and treating it has been mainstream. Immunosuppressant drugs, including thiopurines (azathioprine or 6-mercaptopurine), anti-tumor necrosis factor-α (anti-TNF-α) antibody (infliximab and adalimumab), and calcineurin inhibitor, can be used in treat patients with corticosteroid-dependent and/or corticosteroid-refractory moderate-to-severe UC. Recently, in addition to such a conventional therapeutic agent, golimumab, which is the first transgenic human monoclonal anti-TNF-α antibody to be fabricated, anti α-4/β-7 integrin antibody, and Janus kinase inhibitor have been reported to novel immunosuppressant therapy. Furthermore, other treatments with unique mechanisms different from immunosuppression, have also been suggested, including fecal microbiota transplantation and Indigo naturalis, which is a Chinese herbal medicine. We compared the features and efficacy of these new treatments. In this issue, the features and treatment options for these new treatments is reviewed.
  • Keywords: Colitis, ulcerative; Vedolizumab; Tofacitinib; Indigo naturalis; Fecal microbiota transplantation
Ulcerative colitis (UC) is a chronic inflammatory condition of the GI tract, which is associated with diarrhea, bloody stool, and abdominal pain [1]. Although the cause of UC is postulated to be multifactorial in nature, including genetic predisposition, epithelial barrier defects, dysregulation of immune responses, and environmental factors, the specific pathogenesis of UC is still incompletely understood.
For patients with mild-to-moderate UC, use at oral and topical 5-aminosalicylates (5-ASA) are recommended as a first-line therapy. Patients who do not achieve remission with 5-ASA drugs should be treated with corticosteroids [1]. Although efficacy at 30 days after corticosteroid administration in UC patients was 80%, only 49% maintained clinical response for 1 year, and 22% was steroid dependency [2]. Immunosuppressant drugs, including thiopurines (azathioprine or 6-mercaptopurine), anti-TNF-α antibody, and calcineurin inhibitor, can be used to treat patients with steroid dependency and/or steroid refractory moderate-to-severe UC. Recently, golimumab (GLM), which is the first transgenic human monoclonal anti-TNF-α antibody to be fabricated, anti α-4/β-7 integrin antibody, and Janus kinase (JAK) inhibitor have been reported to novel immunosuppressant therapy. Other treatments with unique mechanisms different from immunosuppression, have also been suggested, including fecal microbiota transplantation (FMT), which improves intestinal microbiota, and Indigo naturalis, which is a Chinese herbal medicine. Our aim in this review was to summarize current evidence and mechanisms of therapeutic effectiveness for current UC therapies.
Anti-TNF-α antibody is key drug to induce and maintenance remission in patients with moderate-to-severe UC. TNF-α is an inflammatory cytokine, being present either as a membrane protein of cells or in soluble form in blood [3]. Anti-TNF-α antibody neutralizes soluble TNF-α and binds membranebound TNF-α to prevent cell damage, Anti-TNF-α antibody also suppresses TNF-α expression by inducing apoptosis of TNF-α producing cells. Since August 2018, anti-TNF-α antibody such as infliximab (IFX), adalimumab (ADA), and GLM, have been available for the treatment of UC, with demonstrated therapeutic efficacy of these drugs in Japan [4-7]. However, a head-to-head comparison of these 3 different drugs has yet to be completed to determine any superiority. However, loss of response (LOR) is an important limitation of these drugs. As an example, among patients with CD treated using anti-TNF-α antibody, LOR develops in about 37% of cases, with 13% of these patients being unable to continue with anti-TNF-α antibody for up to 1 year. The mean percentage of patients with LOR of IFX was 37% and the annual risk for LOR of IFX was calculated to be 13% per patient-year [8]. Thus, many patients on anti-TNF-α antibody therapy will need to change to another treatment for UC at some point over the course of their treatment.
A low trough level of anti-TNF-α antibody and anti-drug (anti-TNF-α antibody) antibody (ATA) have been identified as causes of LOR [9]. There are many reports that optimization of treatment by trough concentration and ATA (treat to target) is effective [10]. For example, Vande Casteele et al. [11] reported that targeting IFX trough level to 3–7 mg/mL by optimizing dose and interval, results in a more efficient use of the drug. Furthermore, after dose optimization, continued concentrationbased dosing was associated with fewer disease relapse during the course of treatment. Although it is a retrospective study, efficacy by increasing the dose of anti-TNF-α antibody in UC has also been reported [12]. However, trough level or ATA cannot be measured in many countries including Japan. In this case, anti-TNF-α antibody is optimized using other biomarkers. Although it is research on CD, CALM trial reported that the proportion of patients with Mucosal healing and steroid free at 48 weeks after entry was higher with early optimization of ADA using biomarkers such as serum CRP and fecal calprotectin [13].
ATA inhibits the binding of anti-TNF-α antibody to the TNF-α molecule, with the resulting immune complex formation increasing the clearance rate of anti-TNF-α antibody which, ultimately, lowers the blood concentration of anti-TNF-α antibody [14,15]. The rate of ATA production among patients with CD after having achieved remission with a 5 mg/kg dose of IFX was evaluated for different doses of maintenance IFX, 5 and 10 mg/kg and compared with a placebo [16]. The rate of ATA production was 10% at an IFX dose of 5 mg/kg and 7% at a dose of 10 mg/kg, compared to 30% in the placebo group. Therefore, the discontinuation of anti-TNF-α antibody therapy may increase the incidence of ATA production and may attenuate the effectiveness of anti-TNF-α antibody therapy when resumed. There is also evidence regarding additional therapeutic effectiveness of combination therapy of immunomodulator (IM) together and IFX to suppress ATA production, as reported in the UC-SUCCESS trial [17]. The efficacy of combining IM with either ADA or GLM remains to be determined. Among anti-TNF-α antibody drugs available, GLM, which is synthesized using a transgenic method, might have a lower rate of ATA production than either IFX or ATA. However, a prospective trial for direct comparison of ATA production and rate of LOR for these 3 anti-TNF-α antibody drugs is needed.
Overall, there is currently no clear evidence to distinguish the selection of IFX, ADA or GLM at this time, with selection being based on clinical criteria, such as route of administration, administration time and frequency of scheduled visits for treatment (Table 1).
Integrins are obligatory type I heterodimers that include α and β subunits and are found on the surface of cells, such as leucocytes. In humans, 18 types of α-subunits and 8 β-subunits have been identified, yielding 24 different types of integrins comprised of different combinations of α and β-subunits. Integrins bind specifically on sites of adhesion which are expressed on vascular endothelial cells, and allow T lymphocytes to migrate into intestinal tissue, where they induce inflammation [18].
Vedolizumab binds to α4β7 integrin on the surface of inflammatory cells, suppressing the migration of T lymphocytes into intestinal tissue, producing an anti-inflammatory effect. Specifically, the α4β7 integrin is a cell-surface glycoprotein that is expressed on T lymphocytes and induces inflammation through its interaction with the mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on intestinal vascular endothelial cells. Because MAdCAM-1 is selectively expressed in the vascular endothelium of the intestinal tract, the action of vedolizumab is probably confined to the intestinal tract.
The efficacy and safety of vedolizumab for induction and maintenance therapy of UC has been reported in the GEMINI-I trial [19]. The GEMINI-I trial is a phase 3, randomized, double-blind, placebo-controlled study of 374 patients with moderate-to-severe UC. To evaluate the effectiveness of vedolizumab for induction of UC remission, patients were randomly assigned to receive intravenous vedolizumab (300 mg) or a placebo, on days 1 and 15. Based on these definitions, the clinical rate of response to vedolizumab was 47.1%, which was higher than the 25.5% rate in the placebo group (P<0.001).
To evaluate the effectiveness of vedolizumab for maintenance therapy, patients who achieved a clinical response at week 6 were randomly assigned to one of the following groups for maintenance therapy: vedolizumab every 8 weeks (with placebo administered every other visit to preserve blinding); vedolizumab every 4 weeks; or placebo. The prescribed treatment was continued for 52 weeks, with the primary outcome being clinical remission, defined as a Mayo Clinic score ≤2 (with no subscore higher than 1) and mucosal healing, defined as an endoscopic subscore of 0 or 1. The rate of clinical remission at 52 weeks was 41.8% for the group receiving vedolizumab every 8 weeks, 44.8% for the group receiving vedolizumab every 4 weeks and 15.9% for the placebo group. Therefore, the rate of clinical remission was higher among patients receiving vedolizumab than the placebo group (P<0.001). No difference in the rate of adverse events was identified in the GEMINI-I trial between the vedolizumab and placebo group (Table 2).
Systematic review showed that clinical response and remission were achieved in 43% and 25% by week 6, respectively, and in 51% and 30% by week 14 to 22. At week 52, clinical response and remission were achieved in 48% and 39% of the patients, respectively. Adverse effects were mostly minor and occurred in 30.6% of the patients [20]. Since the approval of vedolizumab, several real-world experience studies were reported. For example, Kopylov et al. [21] reported that clinical response at week 14 after Vedolizumab administration was 23.5%, at week 52 was 45%. Amiot et al. [22] also showed that the effect of Vedolizumab for UC was better at 14 weeks than at 6 weeks. These results suggested that the effectiveness of Vedolizumab appears slowly in some cases. There are also reports that the use of calcineurin inhibitor and vedolizumab together showed that 64% clinical response was obtained for 52 weeks after the end of calcineurin inhibitor [23]. Namely, because the onset of effect is slow but safety is high, the effectiveness for maintenance therapy after introduction of remission is suggested.
Of note, the use of natalizumab, integrin α4 inhibitor, was associated with progressive multifocal leukoencephalopathy (PML) in clinical trials due to the reactivation of the JC polyoma virus. This was not an issue in the GEMINI-I trial. Moreover, as vedolizumab acts locally on the intestinal tract, the risk of systemic side effects is likely to be quite low. Currently, the long-term safety of vedolizumab is continuing to be evaluated in the GEMINI long-term safety (LTS) study [24].
JAK refers to 4 intracellular types of tyrosine kinase (JAK1, JAK2, JAK3, and tyrosine kinase 2) that activate signal transducers and activators of transcription (STATs). Inflammatory cytokines bind to JAK receptors on cell membranes. As JAK receptors are phosphorylated, they are activated by this binding. The transcription factor STAT is attracted to the phosphorylated JAK receptor and activated. The activated STAT forms a dimer and migrates inside the cell nucleus, initiating gene transcription, and ultimately, the action of the cytokine is exerted. The combination of the 4 types of JAK and 7 types of STAT causes various effects [25]. Tofacitinib inhibits all JAKs, with a more specific and strong inhibitory effect on JAK types 1 and 3. As such, tofacitinib suppresses inflammation via its inhibition of the JAK-STAT system.
The OCTAVE trial provided evidence of the efficacy of tofacitinib in inducing and maintaining disease remission among patients with UC [26]. The OCTAVE induction 1 trial included 598 patients with moderate-to-severe UC. Patients were randomly assigned to the tofacitinib (10 mg twice daily for 8 weeks) or placebo group. The primary outcome was clinical remission at 8 weeks, defined by a total Mayo score of ≤ 2, with no subscore >1, and a rectal bleeding subscore of 0. The rate of remission induction was 18.5% in the tofacitinib group, compared to 8.2% in the placebo group (P=0.007; 95% CI, 4.3–16.3). The OCTAVE induction 2 trial was conducted with 541 patients, again with moderate-to-severe UC, to verify the outcomes of the first phase, using the same criteria for clinical remission. In the OCTAVE induction 2 trial, the rate of remission induction was 16.6% in the tofacitinib group, compared to 3.6% in the placebo group (P<0.001; 95% CI, 8.1–17.9) (Table 3).
To evaluate the efficacy of tofacitinib to maintain disease remission, 593 patients who had achieved a clinical response at 8 weeks in the induction trial, were randomly assigned to the following 3 groups for 52 weeks: oral dose of tofacitinib of 5 mg twice daily, oral dose of 10 mg twice daily and a placebo. In the maintenance phase of the OCTAVE trial. The remission rate at 52 weeks was 34.3% in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group, compared to 11.1% in the placebo group (P<0.001) (Table 3).
Infection is the main side effect of tofacitinib, in the OCTAVE induction 1/2 trial, with an incidence rate of 23.3% and 18.2% for the 10-mg tofacitinib groups, compared to 15.6% and 15.2% in the placebo group. In the OCTAVE sustain trial, the infection rate was 35.9% in the 5-mg tofacitinib group, 39.8% in the 10-mg tofacitinib group and 24.2% in the placebo group. Especially, a Herpes zoster virus infection occurred in 1.5% of infection cases in the 5-mg group, 5.1% in the 10-mg group, and 0.5% in the placebo group. Non-melanoma skin cancer occurred in 5 patients in the tofacitinib group and 1 patient in placebo group. In addition, 5 patients in the tofacitinib group experienced a cardiovascular event, and the incidence of an increase in lipid level was higher in the tofacitinib than placebo group. The mechanism by which tofacitinib induces dyslipidemia is unknown. Chronic inflammation does decrease lipid levels [27], therefore, to be thought that the anti-inflammatory effect of tofacitinib would consequently increase lipid levels [28].
The effectiveness of anti-TNF-α antibody, vedolizumab, and tofacitinib has not been directly compared. Thus, there currently are no clinical guidelines to inform the selection of the most appropriate drug to use, especially for patients who are naïve to anti-TNF-α antibody therapy. The network meta-analysis provided the following surface under the cumulative ranking value regarding the efficacy of biologics in patients with no prior history of anti-TNF-α antibody therapy: IFX, 85%; vedolizumab, 82%; GLM, 58%; tofacitinib, 43%; and ADA, 31% [29]. The associated rate of mucosal healing was as follows: IFX, 91%; vedolizumab, 81%; tofacitinib, 54%; GLM, 41%; and ADA, 32%. In the evaluation of the effectiveness of ADA, vedolizumab and tofacitinib among patients who had a previous history of TNF-α antibody therapy, tofacitinib provided the highest efficacy for achieving both clinical remission and mucosal healing. It is important to note, again, that a head-to-head comparison of each drug was not conducted, which limits the translation of these results to practice.
The comparative efficacy of vedolizumab and anti-TNF-α antibody therapy was reported in a retrospective study at the 13th Congress of the European Crohn’s and Colitis Organisation. Both the clinical remission rate and the endoscopic curative rate, after 12 months from the initiation of therapy with each of the drugs, were compared. The clinical remission rate was 38% for the vedolizumab group, compared to 34% for the anti TNF-α antibody therapy group (HR, 1.27; 95% CI, 0.91–1.78), with an endoscopic healing rate of 50% versus 41%, respectively (HR, 1.67; 95% CI, 1.13–2.47). Although vedolizumab was deemed to be superior to anti-TNF-α antibody, cases of clinical failure on anti-TNF-α antibody therapy were included in the analysis and, as such, the effectiveness of anti-TNF-α antibody may have been underestimated. Therefore, the superiority of vedolizumab, as shown this study, should be interpreted with caution. However, the findings from this study do support the use of vedolizumab for patients who do not achieve a satisfactory response with anti-TNF-α antibody therapy.
Currently, there is insufficient evidence for a preferential selection of vedolizumab over tofacitinib. Tofacitinib has been associated with shingles and other infectious diseases, GI perforation, cardiovascular events, and elevation of serum lipids. Therefore, caution with prescription of this drug is indicated. On the contrary, it is considered that there are few adverse events in vedolizumab.
Based on current evidence, anti-TNF-α antibody therapy and tofacitinib may be considered as first-line biologics for the treatment of patients with severe UC. Furthermore, as there is currently greater evidence regarding the efficacy and safety of anti-TNF-α antibody therapy, compared to tofacitinib, the use of anti-TNF-α antibody therapy may first be considered. Vedolizumab may be used in cases that do not need a prompt induction of disease remission and that should be give priority to safety. In addition, Vedolizumab may be useful for patients who are difficult to maintain after induction of remission.
Indigo naturalis is fabricated from plants, including Indigofera tinctoria and Strobilanthes cusia, and contains both indigo and indirubin. Indole compounds, such as indigo and indirubin, contains an indole ring structure. Indole compounds are ligands for the aryl hydrocarbon receptor (AhR) [30] and act on innate type 3 lymphoid cells, expressing AhR. Recent studies have shown that the AhR signaling pathway stimulates the production of interleukin-22 [31,32], which supports a role for indigo naturalis in the mucosal healing process [33]. Therefore, indigo naturalis could provide an effective AhR ligand for the treatment of UC [34].
Historically, indigo naturalis has been used for the treatment of various inflammatory diseases and dermatitis, in China [35,36], including UC. Few studies have evaluated the therapeutic effectiveness of indigo naturalis for the treatment of UC. Sugimoto et al. [37] reported the effectiveness of indigo naturalis. In this study, clinical response rate of a daily dose of 2.0 g of indigo naturalis for 8 weeks for the treatment of moderate-to-severe UC were 65%. Naganuma et al. [38] performed a prospective, randomized, double blind, placebo controlled trial on the efficacy of indigo naturalis, using a daily dose of 0.5, 1.0, or 2.0 g, for 8 weeks, with a placebo group. The clinical response rate for each of the groups was as follows: 13.6% in the placebo group; 69.6% in the 0.5 g group; 75.0% in the 1.0 g group; and 81.0% in the 2.0 g group (P<0.001 for all indigo naturalis compared to the placebo group). During the time of the study, however, a report was published describing the development of pulmonary artery hypertension (PAH) among several patients who had purchased indigo naturalis without participating in a study. Therefore, Naganuma et al. [38] terminated their trial due to safety considerations.
Adverse effects of indigo naturalis have been reported, including hepatic disorder, headache, nausea, vomiting, abdominal pain, intussusception, non-specific enteritis, and PAH [39]. Several factors can contribute to PAH development, including growth factors, cytokines, metabolic signaling, elastase, protease, and serotonin [40]. Serotonin is a metabolite of tryptophan, an AhR ligand [31]. As indigo is an AhR ligand, than administration of indigo naturalis might increase serotonin expression via the metabolic pathway of tryptophan. As serotonin acts on vascular smooth muscle cells, increases in serotonin levels would lead to the development of PAH. This postulated pathway, linking indigo naturalis to PAH, remains to be verified (Fig. 1A).
Although the relationship between the dose of indigo naturalis and adverse effects is not clear, patients who develop PAH used indigo naturalis over a longer-term period. Adverse effects can be reversibly improved by discontinuing the use of indigo naturalis and/or appropriate therapeutic intervention. Of note, in patients who developed intussusception with the use of indigo naturalis, recurrence was noted with resumption of the use of indigo naturalis [41]. Therefore, it is possible that some indigo naturalis-induced adverse effects could be recurrent.
Currently, as the safety of indigo naturalis has not been clearly established, it should be carefully used in practice, despite its known efficacy. Indigo naturalis should carefully be used for the treatment of patients with UC in whom induction of remission cannot be achieved with the use of corticosteroids, anti-TNF-α antibody therapy or calcineurin inhibitor. Considering that no advantage was found for a dose of indigo naturalis of 2.0 g, compared to 1.0 g, a dose of indigo naturalis of ≤ 1.0 g per day should be used for the treatment of UC, and its use should be limited to 8 weeks to avoid side effects, such as PAH. Moreover, when using indigo naturalis, blood check tests, electrocardiogram, and echocardiogram assessments, among other assessment, should be regularly performed for early identification of adverse effects.
Before indigo naturalis can be used for UC treatment, its mechanisms of action will need to be concretely defined and its active components identified, and strategies to lower the risk of adverse events defined. In our lab, we are currently attempting to reduce the risk of adverse effects by suppressing absorption of indigo naturalis in the small intestine. To achieve this goal, we are attempting to develop indigo naturalis suppositories and capsules that collapse to deliver the dose of indigo naturalis in the large intestine (Fig. 1B and C). We are also planning studies to elucidate how indigo, which is an AhR ligand contained in indigo naturalis, exerts its therapeutic effects on various immune cells, the intestinal epithelium and intestinal bacteria. There is also a need to link our results to drug discovery.
FMT is a unique treatment that specifically improves intestinal microbiota. FMT gained much attention due to its effectiveness in the treatment of Clostridium difficile infection, described in 2013 [42]. Various studies have reported the intestinal microbiota change among patients with IBD. In fecal or intestinal epithelium of UC patients, it has been shown a lower relative level of the Firmicutes genus, such as Clostridium cluster IV and XIVa, with a relative higher proportion of the Bacteroidetes and Proteobacteria genus [43]. However, it is unclear whether these changes in intestinal bacterial are the cause or the result of UC. The effectiveness of FMT for the treatment of UC has been evaluated in different randomized controlled trials. Moayyedi et al. [44] reported a significantly higher remission rate of a 7-week period in the FMT (24%) than the placebo (5%) group. By comparison, Rossen et al. [45] did not identify a therapeutic effectiveness of a 12-week period of FMT therapy, with a remission rate of 30% compared to 20% in the placebo group. Paramsothy et al. [46] reported a therapeutic efficacy, providing FMT therapy 5 days per week for 8 weeks, with a remission rate of 27% compared to 8% in the placebo group (P=0.021 and P=0.021).
Although the effectiveness of FMT for the treatment of UC has been reported in a meta-analysis [47], the optimal protocol for administration (trans-nasally or trans-anal administration, with or without pretreatment antibiotic therapy, and donor eligibility) have remained not to be defined yet.
Although various treatments for IBD have been developed, there is currently insufficient evidence to inform the selection between established and novel treatments. As such, emerging treatments will continue to complicate the clinical management of UC. Furthermore, as treatment options increase, there is concern that patients will favor internal medicine approaches to treatment, which could delay surgical treatment, which can provide a curative effect. Increasingly, there will be a need to fully understand the mechanisms of action of the different therapeutic strategies, and to develop guidelines for treatment selection based on patient-specific characteristics.

FINANCIAL SUPPORT

The authors received no financial support for the research, authorship, and/or publication of this article.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTION

Fukuda T, Naganuma M, and Kanai T contributed to the drafting of the article, and contributed to critical revision of the article for important intellectual content. All the authors approved the final draft of the article.

We thank the present and past members of the Keio IBD Group for their continued support.
Fig. 1.
Administration route of Indigo naturalis. (A) This is a hypothesis of the mechanism of pulmonary artery hypertension (PAH) onset by Indigo naturalis administration. Administration of Indigo naturalis increases the concentration of Indigo in the blood. Indigo acts as an aryl hydrocarbon receptor (AhR) ligand, resulting in an increase in serotonin concentration, a metabolite of tryptophan. Serotonin causes PAH. (B, C) shows an ingenuity of administration method to reduce side effects of Indigo naturalis. (B) The capsules that collapse in the large intestine decrease absorption of Indigo naturalis in the small intestine. (C) Suppository is administered without going through the small intestine.
ir-2018-00126f1.jpg
Table 1.
Difference in Anti-TNF-α Antibodies
Item Infliximab Adalimumab Golimumab
Administration interval (induction phase) At wk 0, 2, 6 Every 2 wk At wk 0, 2, 6
Administration interval (maintenance phase) Every 8 wk Every 2 wk Every 4 wk
Administration route Intravenous administration SC injection SC injection
Self-administration × ○ ×
Efficacy of combination therapy of immunomodulator ○ Unclear Unclear
Table 2.
Efficacy of Vedolizumab in GEMINI Trials
Treatment phase Primary outcome Results
Induction Clinical response at wk 6a 47.1%, 25.5% (receive intravenous vedolizumab or placebo at day 1 and 15), P<0.001
Maintenance Clinical remission at wk 52b 44.8%, 41.8%, 15.9% (300 mg/4 wk, 300 mg/8 wk, placebo), 300 mg/4 wk vs. placebo (P<0.001), 300 mg/8 wk vs. placebo (P<0.001)

a Clinical response defined as a reduction in the Mayo Clinic score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.

b Clinical remission defined as a Mayo Clinic score of 2 or lower and no subscore higher than 1, and mucosal healing, defined as an endoscopic subscore of 0 or 1.

Table 3.
Efficacy of Tofacitinib in OCTAVE Trials
Trial Primary outcome Results
OCTAVE induction 1 (induction) Remission at 8 wka 18.5%, 8.2% (10 mg, placebo), P=0.007
OCTAVE induction 2 (induction) Remission at 8 wka 16.6%, 3.6% (10 mg, placebo), P<0.001
OCTAVE sustain (maintenance) Remission at 52 wka 34.3%, 40.6%, 11.1% (5 mg/BID, 10 mg/BID, placebo), 5 mg/BID vs. placebo (P<0.001) 10 mg/BID vs. placebo (P<0.001)

a Remission defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0.

  • 1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017;389:1756–1770.ArticlePubMed
  • 2. 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;121:255–260.ArticlePubMed
  • 3. Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL. Anti-TNF-alpha therapies: the next generation. Nat Rev Drug Discov 2003;2:736–746.ArticlePubMedPDF
  • 4. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476.ArticlePubMed
  • 5. Adalimumab in the treatment of moderate-to-severe ulcerative colitis: ULTRA 2 trial results. Gastroenterol Hepatol (N Y) 2013;9:317–320.PubMedPMC
  • 6. 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.ArticlePubMed
  • 7. 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.e1.ArticlePubMed
  • 8. Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol 2009;104:760–767.ArticlePubMedPDF
  • 9. Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 2013;108:40–47.ArticlePubMedPDF
  • 10. Sofia MA, Rubin DT. Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis. Therap Adv Gastroenterol 2016;9:548–559.ArticlePubMedPMC
  • 11. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 2015;148:1320–1329.e3.ArticlePubMed
  • 12. Cesarini M, Katsanos K, Papamichael K, et al. Dose optimization is effective in ulcerative colitis patients losing response to infliximab: a collaborative multicentre retrospective study. Dig Liver Dis 2014;46:135–139.ArticlePubMed
  • 13. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 2018;390:2779–2789.Article
  • 14. Imaeda H, Takahashi K, Fujimoto T, et al. Clinical utility of newly developed immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol 2014;49:100–109.ArticlePubMed
  • 15. Imaeda H, Andoh A, Fujiyama Y. Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease. J Gastroenterol 2012;47:136–143.ArticlePubMed
  • 16. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2004;2:542–553.ArticlePubMed
  • 17. Panccione R, Ghosh S, Middleton S, et al. Infliximab, azathioprine, or infliximab + azathioprine for treatment of moderate to severe ulcerative colitis: the UC success trial. Gastroenterology 2011;140:S–134.Article
  • 18. Ley K, Rivera-Nieves J, Sandborn WJ, Shattil S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 2016;15:173–183.ArticlePubMedPMCPDF
  • 19. 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.ArticlePubMed
  • 20. Engel T, Ungar B, Yung DE, Ben-Horin S, Eliakim R, Kopylov U. Vedolizumab in IBD-lessons from real-world experience: a systematic review and pooled analysis. J Crohns Colitis 2018;12:245–257.ArticlePubMedPDF
  • 21. Kopylov U, Avni-Biron I, Ron Y, et al. Effectiveness and safety of vedolizumab for maintenance treatment in inflammatory bowel disease: the Israeli real world experience. Dig Liver Dis 2019;51:68–74.ArticlePubMed
  • 22. 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;14:1593–1601.e2.ArticlePubMed
  • 23. Christensen B, Gibson P, Micic D, et al. Safety and efficacy of combination treatment with calcineurin inhibitors and vedolizumab in patients with refractory inflammatory bowel disease. Clin Gastroenterol Hepatol [published online ahead of print May 8, 2018].https://doi.org/10.1016/j.cgh.2018.04.060.Article
  • 24. Loftus EV Jr, Colombel JF, Feagan BG, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis 2017;11:400–411.ArticlePubMedPDF
  • 25. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 2014;57:5023–5038.ArticlePubMed
  • 26. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723–1736.ArticlePubMed
  • 27. Choy E, Sattar N. Interpreting lipid levels in the context of highgrade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 2009;68:460–469.ArticlePubMed
  • 28. Wu JJ, Strober BE, Hansen PR, et al. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. J Am Acad Dermatol 2016;75:897–905.ArticlePubMed
  • 29. Vickers AD, Ainsworth C, Mody R, et al. Systematic review with network meta-analysis: comparative efficacy of biologics in the treatment of moderately to severely active ulcerative colitis. PLoS One 2016;11:e0165435.ArticlePubMedPMC
  • 30. Adachi J, Mori Y, Matsui S, et al. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J Biol Chem 2001;276:31475–31478.ArticlePubMed
  • 31. 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;39:372–385.ArticlePubMed
  • 32. 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;39:386–399.ArticlePubMed
  • 33. Kawai S, Iijima H, Shinzaki S, et al. Indigo naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation. J Gastroenterol 2017;52:904–919.ArticlePubMedPDF
  • 34. Sugimoto S, Naganuma M, Kanai T. Indole compounds may be promising medicines for ulcerative colitis. J Gastroenterol 2016;51:853–861.ArticlePubMedPDF
  • 35. Lin YK, Wong WR, Chang YC, et al. The efficacy and safety of topically applied indigo naturalis ointment in patients with plaque-type psoriasis. Dermatology 2007;214:155–161.ArticlePubMed
  • 36. Deng S, May BH, Zhang AL, Lu C, Xue CC. Plant extracts for the topical management of psoriasis: a systematic review and meta-analysis. Br J Dermatol 2013;169:769–782.ArticlePubMedPMC
  • 37. 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.ArticlePubMedPMC
  • 38. 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;154:935–947.ArticlePubMedPMC
  • 39. Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J 2016;37:1992.ArticlePubMedPMCPDF
  • 40. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 2011;8:443–455.ArticlePubMedPMCPDF
  • 41. Kondo S, Araki T, Okita Y, et al. Colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-Dai in patients with ulcerative colitis: a report of two cases. Clin J Gastroenterol 2018;11:268–272.ArticlePubMedPMCPDF
  • 42. Razik R, Rumman A, Bahreini Z, McGeer A, Nguyen GC. Recurrence of Clostridium difficile infection in patients with inflammatory bowel disease: the RECIDIVISM study. Am J Gastroenterol 2016;111:1141–1146.ArticlePubMedPDF
  • 43. Nagao-Kitamoto H, Kamada N. Host-microbial cross-talk in inflammatory bowel disease. Immune Netw 2017;17:1–12.ArticlePubMedPMC
  • 44. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015;149:102–109.e6.ArticlePubMed
  • 45. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 2015;149:110–118.e4.ArticlePubMed
  • 46. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017;389:1218–1228.ArticlePubMed
  • 47. Costello SP, Soo W, Bryant RV, Jairath V, Hart AL, Andrews JM. Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis. Aliment Pharmacol Ther 2017;46:213–224.ArticlePubMed

Figure & Data

REFERENCES

    Citations

    Citations to this article as recorded by  
    • Histologic features and predicting prognosis in ulcerative colitis patients with mild endoscopic activity
      Seung Yong Shin, Hee Sung Kim, Kisung Kim, Chang Won Choi, Jung Min Moon, Jeong Wook Kim, Hyun Jin Joo, Jeongkuk Seo, Muhyeon Sung, Chang Hwan Choi
      The Korean Journal of Internal Medicine.2024; 39(1): 68.     CrossRef
    • Recent Updates on the Therapeutics Benefits, Clinical Trials, and Novel Delivery Systems of Chlorogenic Acid for the Management of Diseases with a Special Emphasis on Ulcerative Colitis
      Ranjit K. Harwansh, Hemant Bhati, Rohitas Deshmukh
      Current Pharmaceutical Design.2024; 30(6): 420.     CrossRef
    • Dose-dependent effects of cobalt chloride supplementation in a rat model of acetic acid-induced ulcerative colitis
      Akinleye Stephen Akinrinde, Ekundayo Stephen Samuel, Bisi Olajumoke Adeoye
      Comparative Clinical Pathology.2024; 33(5): 705.     CrossRef
    • Systematical investigation of the mechanism underlying the therapeutic effect of Astragalus membranaceus in ulcerative colitis
      Jingxin Mao, Lihong Tan, Cheng Tian, Wenxiang Wang, YanLin Zou, Zhaojing Zhu, Yan Li
      The American Journal of the Medical Sciences.2024;[Epub]     CrossRef
    • Pharmacogenetics in personalized treatment in pediatric patients with inflammatory bowel disease (IBD)
      Daniela Kosorínová, Pavlína Suchá, Zuzana Havlíčeková, Marek Pršo, Pavol Dvoran, Peter Bánovčin
      Česko-slovenská pediatrie.2024; 79(4): 213.     CrossRef
    • Long‐term safety and efficacy of filgotinib for the treatment of moderately to severely active ulcerative colitis: Interim analysis from up to 4 years of follow‐up in the SELECTION open‐label long‐term extension study
      Brian G. Feagan, Katsuyoshi Matsuoka, Gerhard Rogler, David Laharie, Séverine Vermeire, Silvio Danese, Edward V. Loftus, Ian Beales, Stefan Schreiber, Hyo Jong Kim, Margaux Faes, Angela de Haas, Tomasz Masior, Christine Rudolph, Laurent Peyrin‐Biroulet
      Alimentary Pharmacology & Therapeutics.2024; 60(5): 563.     CrossRef
    • Loganin Ameliorates Acute Kidney Injury and Restores Tofacitinib Metabolism in Rats: Implications for Renal Protection and Drug Interaction
      Hyeon Gyeom Choi, So Yeon Park, Sung Hun Bae, Sun-Young Chang, So Hee Kim
      Biomolecules & Therapeutics.2024; 32(5): 601.     CrossRef
    • Dynamic changes in the gut microbiota composition during adalimumab therapy in patients with ulcerative colitis: implications for treatment response prediction and therapeutic targets
      Han Na Oh, Seung Yong Shin, Jong-Hwa Kim, Jihye Baek, Hyo Jong Kim, Kang-Moon Lee, Soo Jung Park, Seok-Young Kim, Hyung-Kyoon Choi, Wonyong Kim, Woo Jun Sul, Chang Hwan Choi
      Gut Pathogens.2024;[Epub]     CrossRef
    • Protective effect of (E)-(2,4-dihydroxy)-α-aminocinnamic acid, a hydroxy cinnamic acid derivative, in an ulcerative colitis model induced by TNBS
      Astrid Mayleth Rivera Antonio, Itzia Irene Padilla Martínez, Yazmín Karina Márquez-Flores, Alan Hipólito Juárez Solano, Mónica A. Torres Ramos, Martha Cecilia Rosales Hernández
      Bioscience Reports.2024;[Epub]     CrossRef
    • Lactiplantibacillus plantarum BW2013 protects mucosal integrity and modulates gut microbiota of mice with colitis
      Xiaohui Niu, Qian Li, Na Luan, Jia Liu, Michael Zhang, Jun An, Zuming Li, Zhihui Bai, Ran Xia, Zhichao Wu
      Canadian Journal of Microbiology.2023; 69(4): 158.     CrossRef
    • Reviewing not Homer’s Iliad, but “Kai Bao Ben Cao”: indigo dye—the past, present, and future
      Yusuke Yoshimatsu, Tomohisa Sujino, Takanori Kanai
      Intestinal Research.2023; 21(2): 174.     CrossRef
    • Effect and mechanism of total ginsenosides repairing SDS‑induced Drosophila enteritis model based on MAPK pathway
      Hang Su, Yujing Tan, Zhijiang Zhou, Chunjuan Wang, Wei Chen, Jinlong Wang, Haiming Sun
      Experimental and Therapeutic Medicine.2023;[Epub]     CrossRef
    • Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats
      Jong Mun Won, Hyeon Gyeom Choi, So Yeon Park, Jang-Hee Kim, So Hee Kim
      Pharmaceutics.2023; 15(9): 2195.     CrossRef
    • Knowledge, attitude, and practice of patients living with inflammatory bowel disease: A cross-sectional study
      Xiao-Xiao Shao, Lu-Yan Fang, Xu-Ri Guo, Wei-Zhong Wang, Rui-Xin Shi, Dao-Po Lin
      World Journal of Gastroenterology.2023; 29(43): 5818.     CrossRef
    • Biomarker dynamics during infliximab salvage for acute severe ulcerative colitis: C-reactive protein (CRP)-lymphocyte ratio and CRP-albumin ratio are useful in predicting colectomy
      Danny Con, Bridgette Andrew, Steven Nicolaides, Daniel R van Langenberg, Abhinav Vasudevan
      Intestinal Research.2022; 20(1): 101.     CrossRef
    • Efficacy of sigmoidoscopy for evaluating disease activity in patients with ulcerative colitis
      Su Bum Park, Seong-Jung Kim, Jun Lee, Yoo Jin Lee, Dong Hoon Baek, Geom Seog Seo, Eun Soo Kim, Sang-Wook Kim, So Yeong Kim
      BMC Gastroenterology.2022;[Epub]     CrossRef
    • Protective effects of Ligularia fischeri root extracts against ulcerative colitis in mice through activation of Bcl-2/Bax signalings
      Yong-Ping Fu, Huan Yuan, Yan Xu, Ru-Ming Liu, Yi Luo, Jian-Hui Xiao
      Phytomedicine.2022; 99: 154006.     CrossRef
    • Traditional Chinese Medicine Alleviates Ulcerative Colitis via Modulating Gut Microbiota
      Wan Feng, Lei Zhu, Hong Shen, Jin-Yi Wan
      Evidence-Based Complementary and Alternative Medicine.2022; 2022: 1.     CrossRef
    • Risk of Hepatitis B Virus (HBV) Reactivation in Patients with Immune-Mediated Inflammatory Diseases Receiving Biologics: Focus on the Timing of Biologics after Anti-HBV Treatment
      Soo Min Ahn, Jonggi Choi, Byong Duk Ye, Suk-Kyun Yang, Ji Seon Oh, Yong‑Gil Kim, Chang-Keun Lee, Bin Yoo, Sang Hyoung Park, Seokchan Hong
      Gut and Liver.2022; 16(4): 567.     CrossRef
    • Oral beclomethasone dipropionate as an add-on therapy and response prediction in Korean patients with ulcerative colitis
      Kyuwon Kim, Hee Seung Hong, Kyunghwan Oh, Jae Yong Lee, Seung Wook Hong, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang, Byong Duk Ye, Sang Hyoung Park
      The Korean Journal of Internal Medicine.2022; 37(6): 1140.     CrossRef
    • “Two-birds-one-stone” colon-targeted nanomedicine treats ulcerative colitis via remodeling immune microenvironment and anti-fibrosis
      Jiaxin Zhang, Ante Ou, Xueping Tang, Rong Wang, Yujuan Fan, Yuefei Fang, Yuge Zhao, Pengfei Zhao, Dongying Chen, Bing Wang, Yongzhuo Huang
      Journal of Nanobiotechnology.2022;[Epub]     CrossRef
    • Additive effect of probiotics (Mutaflor) on 5-aminosalicylic acid therapy in patients with ulcerative colitis
      Soo-Kyung Park, Sang-Bum Kang, SangSoo Kim, Tae Oh Kim, Jae Myung Cha, Jong Pil Im, Chang Hwan Choi, Eun Soo Kim, Geom Seog Seo, Chang Soo Eun, Dong Soo Han, Dong Il Park
      The Korean Journal of Internal Medicine.2022; 37(5): 949.     CrossRef
    • Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats
      Sung Hun Bae, Hyo Sung Kim, Hyeon Gyeom Choi, Sun-Young Chang, So Hee Kim
      Biomolecules & Therapeutics.2022; 30(6): 510.     CrossRef
    • Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with N-Dimethylnitrosamine-Induced Liver Cirrhosis
      Sung Hun Bae, Hyeon Gyeom Choi, So Yeon Park, Sun-Young Chang, Hyoungsu Kim, So Hee Kim
      Pharmaceutics.2022; 14(12): 2684.     CrossRef
    • Trends in Corticosteroid Prescriptions for Ulcerative Colitis and Factors Associated with Long-Term Corticosteroid Use: Analysis Using Japanese Claims Data from 2006 to 2016
      Katsuyoshi Matsuoka, Ataru Igarashi, Noriko Sato, Yuri Isono, Maki Gouda, Katsuhiko Iwasaki, Ayako Shoji, Tadakazu Hisamatsu
      Journal of Crohn's and Colitis.2021; 15(3): 358.     CrossRef
    • Comparison of Long-Term Outcomes of Infliximab versus Adalimumab Treatment in Biologic-Naïve Patients with Ulcerative Colitis
      Yong Il Lee, Yehyun Park, Soo Jung Park, Tae Il Kim, Won Ho Kim, Jae Hee Cheon
      Gut and Liver.2021; 15(2): 232.     CrossRef
    • Efficacy and Safety of Fecal Microbiota Transplantation and Prospect of Microbe-based Therapies for Inflammatory Bowel Disease
      Hoon Gil Jo, Geom Seog Seo
      The Korean Journal of Gastroenterology.2021; 78(1): 31.     CrossRef
    • The Clinical Features of Inflammatory Bowel Disease in Patients with Obesity
      Seong Kyun Kim, Ho-Su Lee, Beom-Jun Kim, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang, Sang Hyoung Park, Masanao Nakamura
      Canadian Journal of Gastroenterology and Hepatology.2021; 2021: 1.     CrossRef
    • Treatment of inflammatory bowel diseases: focusing on 5-aminosalicylates and immunomodulators
      You Sun Kim
      Journal of the Korean Medical Association.2021; 64(9): 596.     CrossRef
    • Long-term Outcomes after the Discontinuation of Anti-Tumor Necrosis Factor-α Therapy in Patients with Inflammatory Bowel Disease under Clinical Remission: A Korean Association for the Study of Intestinal Disease Multicenter Study
      Joo Hye Song, Eun Ae Kang, Soo-Kyung Park, Sung Noh Hong, You Sun Kim, Ki Bae Bang, Kyeong Ok Kim, Hong Sub Lee, Sang-Bum Kang, Seung Yong Shin, Eun Mi Song, Jong Pil Im, Chang Hwan Choi
      Gut and Liver.2021; 15(5): 752.     CrossRef
    • Treatment of inflammatory bowel diseases: focusing on biologic agents and new therapies
      Hyo Yeop Song, Geom Seog Seo
      Journal of the Korean Medical Association.2021; 64(9): 605.     CrossRef
    • Current status of inflammatory bowel diseases in Korea
      Suk-Kyun Yang
      Journal of the Korean Medical Association.2021; 64(9): 572.     CrossRef
    • Intestinal microbiota and inflammatory bowel diseases
      Chang Soo Eun
      Journal of the Korean Medical Association.2021; 64(9): 588.     CrossRef
    • Does cytomegalovirus load predict the outcome of acute severe ulcerative colitis?
      You Sun Kim
      Intestinal Research.2021; 19(4): 357.     CrossRef
    • Clinical Course of COVID-19 in Patients with Inflammatory Bowel Disease in Korea: a KASID Multicenter Study
      Jin Wook Lee, Eun Mi Song, Sung-Ae Jung, Sung Hoon Jung, Kwang Woo Kim, Seong-Joon Koh, Hyun Jung Lee, Seung Wook Hong, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang, Sang Hyoung Park
      Journal of Korean Medical Science.2021;[Epub]     CrossRef
    • Development of a Machine Learning Model to Distinguish between Ulcerative Colitis and Crohn’s Disease Using RNA Sequencing Data
      Soo-Kyung Park, Sangsoo Kim, Gi-Young Lee, Sung-Yoon Kim, Wan Kim, Chil-Woo Lee, Jong-Lyul Park, Chang-Hwan Choi, Sang-Bum Kang, Tae-Oh Kim, Ki-Bae Bang, Jaeyoung Chun, Jae-Myung Cha, Jong-Pil Im, Kwang-Sung Ahn, Seon-Young Kim, Dong-Il Park
      Diagnostics.2021; 11(12): 2365.     CrossRef
    • Pharmacogenetics-based personalized treatment in patients with inflammatory bowel disease: A review
      Ji Young Chang, Jae Hee Cheon
      Precision and Future Medicine.2021; 5(4): 151.     CrossRef
    • Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation
      Seung Bin Park, Byung-il Choi, Beom Jae Lee, Nam Joo Kim, Yoon A. Jeong, Moon Kyung Joo, Hyo Jung Kim, Jong-Jae Park, Jae Seon Kim, Yoon-Seok Noh, Hyun Joo Lee
      Digestive Diseases and Sciences.2020; 65(8): 2284.     CrossRef
    • Simple determination and quantification of tofacitinib, a JAK inhibitor, in rat plasma, urine and tissue homogenates by HPLC and its application to a pharmacokinetic study
      Ji Eun Kim, Mun Young Park, So Hee Kim
      Journal of Pharmaceutical Investigation.2020; 50(6): 603.     CrossRef
    • Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats
      Eun Hye Gwak, Hee Young Yoo, So Hee Kim
      Biomolecules & Therapeutics.2020; 28(4): 361.     CrossRef
    • Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion
      Sung Hun Bae, Sun-Young Chang, So Hee Kim
      Pharmaceutics.2020; 12(8): 714.     CrossRef
    • The amelioration of ulcerative colitis induced by Dinitrobenzenesulfonic acid with Radix Hedysari
      Gengen Shi, Donghan Wang, Zhiyuan Xue, Xianglin Zhou, Yaoyao Fang, Shilan Feng, Lianggong Zhao
      Journal of Food Biochemistry.2020;[Epub]     CrossRef
    • Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism
      Ji Sang Lee, So Hee Kim
      Pharmaceutics.2019; 11(7): 318.     CrossRef
    • Dermatologische Komplikationen unter Therapie mit Biologika bei entzündlichen Autoimmunerkrankungen
      Wiebke Sondermann, Saskia Herz, Elsa Sody, Andreas Körber
      JDDG: Journal der Deutschen Dermatologischen Gesellschaft.2019; 17(10): 1029.     CrossRef
    • Dermatological complications of therapy with biologics in inflammatory autoimmune diseases
      Wiebke Sondermann, Saskia Herz, Elsa Sody, Andreas Körber
      JDDG: Journal der Deutschen Dermatologischen Gesellschaft.2019; 17(10): 1029.     CrossRef

    • PubReader PubReader
    • ePub LinkePub Link
    • Cite
      CITE
      export Copy Download
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.
      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Current new challenges in the management of ulcerative colitis
      Intest Res. 2019;17(1):36-44.   Published online January 25, 2019
      DOI: https://doi.org/10.5217/ir.2018.00126
      Close
    • XML DownloadXML Download
    Figure
    • 0
    Related articles
    Current new challenges in the management of ulcerative colitis
    Image
    Fig. 1. Administration route of Indigo naturalis. (A) This is a hypothesis of the mechanism of pulmonary artery hypertension (PAH) onset by Indigo naturalis administration. Administration of Indigo naturalis increases the concentration of Indigo in the blood. Indigo acts as an aryl hydrocarbon receptor (AhR) ligand, resulting in an increase in serotonin concentration, a metabolite of tryptophan. Serotonin causes PAH. (B, C) shows an ingenuity of administration method to reduce side effects of Indigo naturalis. (B) The capsules that collapse in the large intestine decrease absorption of Indigo naturalis in the small intestine. (C) Suppository is administered without going through the small intestine.

    Fig. 1.

    Current new challenges in the management of ulcerative colitis
    Item Infliximab Adalimumab Golimumab
    Administration interval (induction phase) At wk 0, 2, 6 Every 2 wk At wk 0, 2, 6
    Administration interval (maintenance phase) Every 8 wk Every 2 wk Every 4 wk
    Administration route Intravenous administration SC injection SC injection
    Self-administration × ○ ×
    Efficacy of combination therapy of immunomodulator ○ Unclear Unclear
    Treatment phase Primary outcome Results
    Induction Clinical response at wk 6a 47.1%, 25.5% (receive intravenous vedolizumab or placebo at day 1 and 15), P<0.001
    Maintenance Clinical remission at wk 52b 44.8%, 41.8%, 15.9% (300 mg/4 wk, 300 mg/8 wk, placebo), 300 mg/4 wk vs. placebo (P<0.001), 300 mg/8 wk vs. placebo (P<0.001)
    Trial Primary outcome Results
    OCTAVE induction 1 (induction) Remission at 8 wka 18.5%, 8.2% (10 mg, placebo), P=0.007
    OCTAVE induction 2 (induction) Remission at 8 wka 16.6%, 3.6% (10 mg, placebo), P<0.001
    OCTAVE sustain (maintenance) Remission at 52 wka 34.3%, 40.6%, 11.1% (5 mg/BID, 10 mg/BID, placebo), 5 mg/BID vs. placebo (P<0.001) 10 mg/BID vs. placebo (P<0.001)
    Table 1. Difference in Anti-TNF-α Antibodies

    Table 2. Efficacy of Vedolizumab in GEMINI Trials

    Clinical response defined as a reduction in the Mayo Clinic score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.

    Clinical remission defined as a Mayo Clinic score of 2 or lower and no subscore higher than 1, and mucosal healing, defined as an endoscopic subscore of 0 or 1.

    Table 3. Efficacy of Tofacitinib in OCTAVE Trials

    Remission defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0.

    Table 1.

    Table 2.

    Table 3.

    Intest Res : Intestinal Research
    © Korean Association for the Study of Intestinal Diseases.
    Close layer
    TOP