1 American Gastroenterological Association Technical Review on the Management of Mild to Moderate Ulcerative Colitis Siddharth Singh, MD, MS 1 *; Joseph D. Feuerstein, MD 2 *; David G. Binion, MD 3 ; William J. Tremaine, MD 4 1 Division of Gastroenterology, University of California, San Diego, La Jolla, CA, 2 Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, MA; 3 Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA; 4 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN *Both authors contributed equally to this manuscript Address for Correspondence: Chair, Clinical Guidelines Committee, American Gastroenterological Association National Office, 4930 Del Ray Avenue, Bethesda, Maryland 20814. E-mail: [email protected]Telephone: (301) 941-2618 Manuscript Word Count: 12,598 References: 216 Tables and Figures: 21+0 eTables and eFigures (in the supplement): 0+50 Disclosures: Siddharth Singh is supported by the American College of Gastroenterology Junior Faculty Development Award and the Crohn’s and Colitis Foundation Career Development Award, and has received an independent research grant from Pfizer and AbbVie. Acknowledgements: The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.
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American Gastroenterological Association Technical Review on the Management of Mild to Moderate Ulcerative Colitis
Siddharth Singh, MD, MS1*; Joseph D. Feuerstein, MD2*; David G. Binion, MD3;
William J. Tremaine, MD4 1Division of Gastroenterology, University of California, San Diego, La Jolla, CA, 2Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, MA; 3Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA; 4Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN *Both authors contributed equally to this manuscript Address for Correspondence: Chair, Clinical Guidelines Committee, American Gastroenterological Association National Office, 4930 Del Ray Avenue, Bethesda, Maryland 20814. E-mail: [email protected] Telephone: (301) 941-2618 Manuscript Word Count: 12,598 References: 216 Tables and Figures: 21+0 eTables and eFigures (in the supplement): 0+50
Disclosures: Siddharth Singh is supported by the American College of Gastroenterology Junior Faculty Development Award and the Crohn’s and Colitis Foundation Career Development Award, and has received an independent research grant from Pfizer and AbbVie.
Acknowledgements: The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.
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ABSTRACT
Most patients with ulcerative colitis (UC) have mild to moderate disease activity,
with low risk of colectomy, and are managed by primary care physicians or
gastroenterologists. Optimal management of these patients decreases the risk of
relapse and proximal disease extension, and may prevent disease progression,
complications and need for immunosuppressive therapy. With several
Clostridium butyricum, and Bacillus mesentericus and VSL#3 have been studied.
Based on evidence synthesized above, the benefit of probiotics for induction and
maintenance of remission over placebo and over mesalamine is uncertain.
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Benefit over placebo for induction of remission was observed in three trials using
VSL#3; however, no trials of maintenance therapy with VSL#3 were identified.
Even though probiotics are well tolerated, in the absence of clear evidence of
benefit, there is potential for harm since use of probiotics may delay use of more
effective therapy. There is limited regulation of quality of probiotic formulations.
Question 11. In patients with mild-moderate UC despite 5-ASA therapy,
what is the role of curcumin for induction and maintenance of remission?
Key Message: In patients with mild-moderate UC despite 5-ASA therapy,
the benefit of adding oral curcumin for induction of remission is unclear (very low
quality evidence), but it may be beneficial for maintenance of remission (low
quality evidence).
Effect Estimates: Based on 3 RCTs with 169 patients with mild-moderate UC
despite standard-dose mesalamine, there was a trend towards benefit with
addition of oral curcumin over placebo for induction of clinical remission, though it
did not reach statistical significance (RR, 0.70 [0.48-1.03]) (eFigure 48).203-205
One trial of curcumin enema also showed comparable effect estimates.206 There
was considerable heterogeneity in effect estimates, with one trial using curcumin
3g/d (containing 95% curcuminoid) showing markedly beneficial effect and
another trial using low dose curcumin 150mg/d, showing no benefit. In a single
trial of maintenance therapy in mesalamine-treated patients with quiescent UC,
addition of oral curcumin was more effective than placebo in maintaining
remission over 6 months (failure to maintain remission: 4/45 [8.9%] vs. 13/44
[29.5%]; RR, 0.30 [0.11-0.85]).207
Quality of evidence: Overall, the body of evidence favoring oral curcumin over
placebo for induction of remission with active mild-moderate UC despite 5-ASA,
was rated as very low quality due to high risk of bias in included trials
(inadequate blinding, allocation concealment, protocol violation, and an
unexpectedly low placebo remission rate), inconsistency (statistically, in
summary estimate, and clinically, with studies using widely variable curcumin
dosage), and imprecision (Table 20). In contrast, evidence supporting the use
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curcumin 2g/d for maintenance of remission in 5-ASA treated patients with
quiescent UC was rated as low quality due to imprecision and risk of bias.
Potential harms of intervention: Curcumin is well tolerated without any
significant treatment-related side effects. However, the potential benefit of using
curcumin for induction of remission in patients sub-optimally controlled on 5-ASA
should be weighed against risks of delaying more effective therapy. Similarly,
when curcumin is added to 5-ASA for maintenance of remission, it’s potential
benefit should be weighed in the context of risk of relapse – for patients at low
risk of relapse maintained on 5-ASA, adding curcumin increases pill burden and
may contribute to inconvenience; for patients at high risk of relapse on 5-ASA,
adding curcumin may potentially delay initially of a more effective, albeit probably
immunosuppressive therapy.
Discussion: Similar to the general population, patients with UC also frequently
use complimentary and alternative therapies with the hope of controlling disease
using a ‘natural’, non-toxic approach.208 While several herbal and dietary
supplements have been studied albeit in poorly designed studies, curcumin, a
naturally occurring phenol, active yellow pigment of turmeric, belonging to the
ginger family is one of the best studied. Biologically, curcumin has
immunomodulating, proapoptotic, and antiangiogenic properties that make it
potentially beneficial in patients with immune-mediated diseases.209 However,
literature on use of curcumin in IBD has been limited by lack of dose-finding
efficacy studies, inability to develop a true placebo indistinguishable from
curcumin (due to taste and color of curcumin), and small study size. In the study
by Lang et al, which was the only strongly positive study of curcumin for induction
of remission, there was exceptionally low placebo remission (0%) and response
(12.5%) rate, unlike that seen in other trials in patients with mild-moderate UC.205
Additionally, the majority of patients in this trial had normal serum inflammatory
markers and may have had mild as opposed to moderate disease activity. Large,
well-designed, phase II or III studies of curcumin are warranted in patients with
mild-moderate UC, who do not adequately respond to induction therapy with
optimized 5-ASA therapy, to adequately inform its role in these patients.
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Similarly, larger studies confirming relative and absolute efficacy of add-on
curcumin for maintaining remission in 5-ASA-treated patients are warranted, to
inform its role in maintenance of remission.
Question 12. In patients with mild-moderate UC, what is the role fecal
microbiota transplantation for induction and maintenance of remission?
Key Message: In patients with mild-moderate UC, fecal microbiota
transplantation may be effective for induction of remission (low quality evidence),
but there is very limited data to inform its role for maintenance of remission.
Effect Estimates: Four RCTs in 281 patients with active UC despite usual care
comparing FMT with placebo were identified; most patients had mild-moderate
disease activity at time of enrollment.210-213 The studies were heterogeneous in
design with inclusion criteria, route of FMT administration and follow-up periods
varying between studies. FMT was delivered via colonoscopy (x1) followed by
enemas (x2 in study by Costello et al;210 x39 administered 5 days/week for 8
weeks in study by Paramsothy et al212) in the two Australian studies, via enemas
(weekly, for 6 weeks)211 or nasoduodenal tube (x2, every 3 weeks)213 in one each
of the other studies. Patient follow-up periods varied from 7 to 12 weeks. In two
studies, stool was obtained from a single donor, whereas in two Australian
studies, stool was pooled from 3-7 donors, and included a mix of fresh and/or
frozen stool; varying quantities of stool was instilled ranging from 8.3g to 120g.
Comparator was either autologous stool in two trials and water in two trials.
Based on meta-analysis of these 4 trials, FMT was more effective than placebo
at inducing clinical remission over a 6-12 week period (RR, 0.80 [0.71-0.89])
(eFigure 49) and endoscopic remission (RR, 0.77 [0.63-0.93]) without significant
heterogeneity. FMT was well tolerated with similar rates of adverse events in the
FMT and placebo groups (RR, 1.41 [0.55-3.60]) (eFigure 50). No trials evaluating
the efficacy of FMT for maintenance of remission were identified. From a recent
meta-analysis of FMT in ulcerative colitis, 5 non-comparative cohort studies on
long-term effectiveness of FMT were identified.214 In these studies, of 44 patients
who underwent 1-5 FMT treatments at time of active disease and were followed
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from 4-72 months, 22 patients had clinical response, 16 patients were
unchanged and 3 patients deteriorated.
Quality of evidence: The overall body of evidence supporting benefit of FMT
over placebo for induction of remission was rated as low quality. Evidence was
rated down for inconsistency (variability in intervention, with differences in route
and frequency of administration, amount and source of stool) and imprecision
(small sample size with low event rate) (Table 21). Though patients in these trials
were along the entire spectrum of UC severity with a substantial proportion on
immunomodulators and/or biologic agents, we did not rate down for indirectness
since the majority of patients had mild-moderately active disease at enrollment,
and the anticipated benefits are likely to be exaggerated in a population with
milder disease, as compared to patients with severe disease (who are inherently
more treatment resistance).
Potential harms of intervention: In RCTs, FMT was well tolerated with very low
rates of serious adverse events (worsening colitis seen in 3/140 patients
receiving FMT vs. 4/137 patients receiving placebo). In a meta-analysis of 50
studies of FMT for UC or alternative reasons (mainly recurrent Clostridium
difficile infection), FMT was well tolerated, with the most common FMT-
attributable adverse event being abdominal discomfort.215 The incidence of FMT-
attributable adverse events was 43.6% (89/204) and 17.7% (76/430) for FMT
delivered through upper and lower gastrointestinal routes, respectively. A total of
44 kinds of serious adverse events were reported in 9.2% patients, including
death (3.5%, 38/1089), infection (2.5%, 27/1089), relapse of IBD (0.6%, 7/1089)
and Clostridium difficile infection (0.9%, 10/1089). Besides direct FMT-
attributable risks, risks of potentially ineffective therapy and delay in initiation of
proven effective therapies are conceivable.
Discussion: With increasing recognition of the role of dysbiosis in the
pathogenesis of IBD, FMT is an attractive intervention. While FMT has
established itself as highly effective in the management of recurrent C.difficile
infection, FMT for the treatment of UC is still experimental. As noted above in 4
small RCTs, there is low quality evidence supporting a beneficial effect of FMT.
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Each trial used different stool processing and delivery protocols, with varying
intensity and variable donor pool, which makes it difficult to recommend a
particular protocol or technique over the other. The mechanism of action of FMT
in UC is unclear. Besides generally increasing bacterial diversity, certain patterns
of microbial changes have been associated with response to FMT in patients with
UC. For example, an increase in Clostridium clusters IV and XVIII was observed
in those who responded in two RCTs and Bacteroidetes including Sutterela spp
and Fusobacterium spp have been associated with non-response to FMT.211, 212
How these changes in microbial composition result in a beneficial effect in some
patients with UC is unclear, and may be related to functional alterations in
luminal and epithelial metabolic and biochemical processes as well as mucosal
immune responses to the microbiota. Overall, this new treatment approach
warrants in-depth mechanistic as well as large-scale clinical evaluation.
KNOWLEDGE GAPS AND FUTURE DIRECTIONS
While several significant advancements have been made in the treatment of
patients with mild-moderate UC, this technical review identified some key
knowledge gaps which merit further evaluation.
1. Risk stratification: Better approaches to identify patients presenting with
moderate symptoms but at high-risk of progression and evolution into a
severe phenotype and development of disease-related complications are
warranted. Though there is some understanding of various clinical,
biochemical and endoscopic factors that may be associated with
progression, there is lack of validated risk prediction models that may
identify high-risk patients early in their disease course. Once these tools
are available, comparative studies on gradual step therapy vs. early
aggressive therapy in patients deemed to have mild-moderate disease
activity would inform an optimal treatment approach.
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2. Impact of 5-ASA on natural history of disease: Though 5-ASA forms the
mainstay of treatment in patients with mild-moderate UC for induction and
maintenance of remission, there is limited understanding on whether these
medications given as maintenance therapy beyond 12 months, modify the
natural history of disease, preventing disease progression and
complications. Likewise, there is little evidence to inform whether 5-ASA
therapy should be continued vs. stopped in patients who escalate to
biologic therapy for moderate-severe UC.
3. Dosing regimens for 5-ASA: While plenty is known (and summarized
above) regarding optimal use of 5-ASA therapies in patients with mild-
moderate UC, there are important knowledge gaps to identify patients who
may benefit from early use of high-dose 5-ASA or in combination with
rectal therapy, rather than gradually stepping from standard 5-ASA
therapy. Additionally, there is limited evidence regarding optimal
maintenance 5-ASA dosing in patients who required high-dose 5-ASA to
induce remission
4. Escalating from 5-ASA therapy to immunosuppressive agents: There is
little evidence to inform when 5-ASA-treated patients should be escalated
to immunosuppressive therapy, particularly for a subset of patients who
intermittently require corticosteroids – for example, should all patients who
require corticosteroids even once after maximal optimization of 5-ASA
therapy, be escalated to immunosuppressive therapy vs. only patients with
continued corticosteroid-dependence or frequent courses of
corticosteroids (≥1 course/year, etc.).
Besides these questions, there are knowledge gaps pertaining to the use of FMT
in patients with UC, for which there are several ongoing studies. Well-designed
trials of probiotic therapy and food supplements such as curcumin would also be
helpful to optimally inform whether these medications are effective for inducing
and/or maintaining remission in patients with mild-moderate UC.
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200. Rembacken BJ, Snelling AM, Hawkey PM, et al. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: A randomised trial. Lancet 1999;354:635-639.
201. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004;53:1617-1623.
202. Zocco MA, Dal Verme LZ, Cremonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Alimentary Pharmacology and Therapeutics 2006;23:1567-1574.
203. Banerjee R PA, Medaboina K, Boramma GG, Amsrala S, Reddy DN. Novel Bio-Enhanced Curcumin with Mesalamine for Induction of Remission in Mild to Moderate Ulcerative Colitis. Gastroeneterology 2017;152:S587.
204. Kedia S, Bhatia V, Thareja S, et al. Low dose oral curcumin is not effective in induction of remission in mild to moderate ulcerative colitis: Results from a randomized double blind placebo controlled trial. World J Gastrointest Pharmacol Ther 2017;8:147-154.
205. Lang A, Salomon N, Wu JCY, et al. Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Clinical Gastroenterology and Hepatology 2015;13:1444-1449.e1.
206. Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis - A randomized, placebo-controlled, pilot study. Journal of Crohn's and Colitis 2014;8:208-214.
207. Hanai H, Iida T, Takeuchi K, et al. Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial. Clinical Gastroenterology and Hepatology 2006;4:1502-1506.
208. Cheifetz AS, Gianotti R, Luber R, et al. Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases. Gastroenterology 2017;152:415-429 e15.
209. Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol 2017;174:1325-1348.
210. Costello SP WO, Bryant RV, Katsikeros R, Makanyanga J, Schoeman M, Mountifield RE, Tee D, Howell S, Hughes PA, Conlon M, Roberts-Thomson IC, Andrews JM. Short Duration, Low Intensity, Pooled Fecal Microbiota Transplantation Induces Remission in Patients with Mild-Moderately Active Ulcerative Colitis: A Randomised Controlled Trial. Gastroeneterology 2017;152:S198-S199.
211. 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.
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212. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. The Lancet 2017;389:1218-1228.
213. 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.
214. Costello SP, Soo W, Bryant RV, et al. Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis. Alimentary Pharmacology and Therapeutics 2017;46:213-224.
215. Wang S, Xu M, Wang W, et al. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PLoS One 2016;11:e0161174.
216. Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 2003;17:29-42.
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S# Focused Question PICO Question Patients Intervention Comparator Outcomes1. In adults with extensive mild-
moderate ulcerative colitis, what dose of mesalamine is effective for induction and maintenance of remission?
Adults with extensive, mild-moderate UC, treated with mesalamine
2. In adults with extensive mild-moderate ulcerative colitis, are diazo-bonded 5-ASA (balsalazide, olsalazine) effective for induction and maintenance of remission?
4. In adults with mild-moderate UC, is combined oral and rectal 5-ASA therapy superior to oral 5-ASA therapy for induction and maintenance of remission?
5. In patients with extensive mild-moderate ulcerative colitis treated with mesalamine, is once-daily mesalamine comparable to multiple times daily administration of mesalamine?
Adults with extensive, mild-moderate UC, treated with oral mesalamine
Once-daily mesalamine Equivalent doses of mesalamine split into two or more doses per day
7. In adults with mild-moderate left-sided colitis or ulcerative proctitis, is oral 5-ASA therapy superior to topical 5-ASA therapy for induction and maintenance of remission?
Adults with mild-moderate UC extending up to splenic flexure (left-sided) or ulcerative proctitis
8. In adults with mild-moderate left-sided UC, what is the role of mesalamine enemas and/or corticosteroid enemas/foam for induction and maintenance of remission?
Adults with mild-moderate UC extending up to splenic flexure (left-sided)
Mesalamine enemas, foam or gel
First- and second-generation corticosteroid enemas or foam
9. In adults with mild-moderate ulcerative proctitis, what is the role of mesalamine suppository and/or corticosteroid suppository for induction and maintenance of remission?
Table 1. Focused clinical questions on the management of mild-moderate ulcerative colitis, and corresponding questions in PICO format addressed in this technical review
65
Formulations Drug Names (tablet strength)
Mode of Delivery Site of Delivery
Dosing range (5-ASA equivalence)
Sulfasalazine Azulfidine (500mg),
Salazopyrin5-ASA linked to sulfapydrine
by azo-bondColon 2-4g/d
(=0.8-1.6g/d 5-ASA)
Diazo-bonded 5-ASA
Olsalazine (Dipentum, 250mg)
5-ASA dimer linked by azo-bond
Colon 2-3g/d (=1.6-2.4g/d 5-ASA)
Balsalazide (Colazaal, 750mg)
5-ASA linked to 4-aminobenzoyl-β-alanine by
azo-bond
Colon 2-6.75g/d (=0.7-2.4g/d 5-ASA)
Mesalamine
pH-dependent release: Delzicol (400mg), Asacol-
HD (800mg)
Eudragit-S coated tables (released at pH ≥7.0)
Terminal ileum, colon
1.6-4.8g/d (=1.6-4.8g/d 5-ASA)
Time-dependent release: Pentasa (250mg, 500mg)
Ethylcellulose-coated microgranules
Duodenum, jejunum,
ileum, colon
1.5-4g/d (=0.8-3.0g/d 5-ASA)
MMX mesalamine: Lialda (1200mg)
Enteric coating (dissolves at pH ≥7.0), MMX of lipophilic and hydrophilic excepients
Terminal ileum, colon
1.2-4.8g/d (=1.2-4.8g/d 5-ASA)
Delayed and extended release mesalamines:
Apriso (375mg) [approved only for
maintenance therapy]
Mesalamine granules in polymer matrix with rnteric
coating (dissolves at pH ≥6.0)
Mid-ileum, colon
1.5g/d (=2.4g/d 5-ASA)
[Abbreviations: 5-ASA=5-aminosalicylate; MMX=Multimatrix] Table 2. Different 5-aminosalicylate formulations with comparable dosing adapted from Sandborn et al216 and Ye et al217
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LOW-DOSE MESALAMINE (<2g/day) COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 900 per 1,000 675 per 1,000 (539 to 714)
RR 0.75 (0.65 to 0.86)
225 fewer per 1,000 (from 126 fewer to 198 fewer)
1138 (8 RCTs)
HIGH
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since optimal information size not met (<200 events) Table 3. GRADE Evidence Profile comparing different doses of mesalamine with placebo for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
67
STANDARD-DOSE MESALAMINE (2-3g/day) vs. LOW-DOSE MESALAMINE (<2g/day) FOR MILD-MODERATE ULCERATIVE COLITIS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with low-dose mesalamine
Risk with high-dose mesalamine
Failure to induce remission 634 per 1,000 612 per 1,000 (555 to 695)
RR 0.81 (0.71 to 0.92)
120 fewer per 1,000 (from 51 fewer to 184 fewer)
519 (6 RCTs)
HIGH
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since 95% CI approaches unity Table 4. GRADE Evidence Profile comparing standard- and high-dose mesalamine with low-dose mesalamine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
68
HIGH-DOSE MESALAMINE (>3g/day) vs. STANDARD-DOSE MESALAMINE (2-3g/day) FOR MILD-MODERATE ULCERATIVE COLITIS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with standard-dose mesalamine
Risk with high-dose mesalamine
Failure to induce remission 678 per 1,000 612 per 1,000 (555 to 695)
RR 0.94 (0.88 to 1.01)
41 fewer per 1,000 (from 7 more to 81 fewer)
2482 (12 RCTs)
◯1 MODERATE
Failure to maintain remission 490 per 1,000 456 per 1,000
(358 to 574) RR 0.93 (0.73 to 1.17)
34 fewer per 1,000 (from 83 more to 132 fewer)
1798 (4 RCTs)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since 95% CI crosses 1 Table 5. GRADE Evidence Profile comparing high-dose mesalamine with standard-dose mesalamine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
69
DIAZO-BONDED 5-AMINOSALICYLATES COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for inconsistency 3Rated down forindirectness (trials used only low-dose mesalamine, as opposed to standard-dose mesalamine) 4Rated down forindirectness (very limited data on balsalazide which may be the preferred diazo-bonded 5-ASA given higher intolerability with olsalazine due to diarrhea) Table 6. GRADE Evidence Profile comparing diazo-bonded 5-aminosalicylates with placebo, standard-dose mesalamine and sulfasalazine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
71
SULFASALAZINE COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with standard-dose mesalamine
Risk with sulfasalazine
Failure to induce remission 383 per 1,000 487 per 1,000 (360 to 663)
RR 1.27 (0.94 to 1.73)
104 more per 1,000 (from 23 fewer to 280 more)
571 (5 RCTs)
◯1 MODERATE
Failure to maintain remission 324 per 1,000 366 per 1,000
(294 to 453) RR 1.13 (0.91 to 1.40)
42 more per 1,000 (from 29 fewer to 129 more)
609 (6 RCTs)
◯◯1,3 LOW
Discontinuation of induction therapy due to adverse events (Tolerability; Important outcome)
49 per 1,000 76 per 1,000 (31 to 185)
RR 1.55 (0.64 to 3.77)
27 more per 1,000 (from 18 fewer to 136 more)
270 (3 RCTs)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for inconsistency 3Rated down forindirectness (most trials used low-dose mesalamine as comparator, as opposed to standard-dose mesalamine)
72
Table 7. GRADE Evidence Profile comparing sulfasalazine with placebo and standard-dose mesalamine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
73
ORAL+RECTAL 5-ASA COMPARED TO ORAL 5-ASA ALONE FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 568 per 1,000 386 per 1,000 (278 to 534)
RR 0.68 (0.49 to 0.94)
182 fewer per 1,000 (from 34 fewer to 290 fewer)
321 (4 RCTs)
◯1 MODERATE
Failure to maintain remission 673 per 1,000 303 per 1,000
(135 to 653) RR 0.45 (0.20 to 0.97)
370 fewer per 1,000 (from 20 fewer to 539 fewer)
96 (2 RCTs)
◯◯1,2 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for indirectness (comparator group received low-dose mesalamine, whereas combined mesalamine amount in intervention group exceeded 2g) Table 8. GRADE Evidence Profile comparing oral+rectal 5-aminosalicylates with oral 5-aminosalicylates alone for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
74
ONCE-DAILY COMPARED TO MULTIPLE-TIMES DAILY MESALAMINE FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 477 per 1,000 458 per 1,000 (405 to 515)
RR 0.96 (0.85 to 1.08)
19 fewer per 1,000 (from 38 more to 72 fewer)
944 (4 RCTs)
◯1 MODERATE
Failure to maintain remission 281 per 1,000 269 per 1,000
(238 to 300) RR 0.96 (0.85 to 1.07)
11 fewer per 1,000 (from 20 more to 42 fewer)
4465 (11 RCTs)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision Table 9. GRADE Evidence Profile comparing once-daily mesalamine with multiple-times daily mesalamine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
75
BUDESONIDE MMX COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with placebo (median)
Risk with controlled ileal-release budesonide
Failure to induce remission 900 per 1,000 837 per 1,000 (783 to 891)
RR 0.93 (0.87 to 0.99)
63 fewer per 1,000 (from 9 fewer to 117 fewer)
255 (1 RCT)
◯◯1,2 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since optimal information size not met (<200 events) 2Rated down for risk of bias Table 10. GRADE Evidence Profile comparing budesonide MMX and controlled ileal-release budesonide with placebo for induction of remission in patients with mild-moderate ulcerative colitis
76
BUDESONIDE MMX COMPARED TO CONTROLLED ILEAL-RELEASE (CIR) BUDESONIDE FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 452 per 1,000 605 per 1,000 (492 to 741)
RR 1.34 (1.04 to 1.64)
154 more per 1,000 (from 41 more to 289 more)
343 (1 RCT)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for risk of bias Table 11. GRADE Evidence Profile comparing budesonide MMX with controlled ileal-release budesonide and standard-dose mesalamine for induction of remission in patients with mild-moderate ulcerative colitis
77
BUDESONIDE MMX (second-generation corticosteroids) COMPARED TO SYSTEMIC CORTICOSTEROIDS FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 771 per 1,000 802 per 1,000 (740 to 871)
RR 1.04 (0.96 to 1.13)
31 more per 1,000 (from 31 fewer to 100 more)
559 (3 RCTs)
◯◯1,2 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for indirectness (all trials compared non-budesonide MMX second-generation corticosteroids with oral prednisone/prednisolone) Table 12. GRADE Evidence Profile comparing MMX vs. oral prednisone/prednisolone, for induction of remission in patients with mild-moderate ulcerative colitis
78
ADDING BUDESONIDE MMX COMPARED TO PLACEBO IN PATIENTS WITH ORAL MESALAMINE-REFRACTORY MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 933 per 1,000 887 per 1,000 (831 to 933)
RR 0.95 (0.89 to 1.00)
47 fewer per 1,000 (from 0 fewer to 103 fewer)
510 (1 RCT)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision Table 13. GRADE Evidence Profile comparing adding budesonide MMX to mesalamine vs. placebo, for induction of remission in patients with oral mesalamine-refractory mild-moderate ulcerative colitis
79
RECTAL 5-ASA COMPARED TO ORAL 5-ASA FOR MILD-MODERATE ULCERATIVE PROCTOSIGMOIDITIS OR PROCTITIS
Failure to induce remission 450 per 1,000 193 per 1,000 (63 to 589)
RR 0.43 (0.14 to 1.31)
256 fewer per 1,000 (from 139 more to 387 fewer)
213 (4 RCTs)
◯◯◯1,2,3 VERY LOW
Failure to maintain remission 369 per 1,000 255 per 1,000
(151 to 432) RR 0.69 (0.41 to 1.17)
114 fewer per 1,000 (from 63 more to 218 fewer)
129 (3 RCTs)
◯◯◯1,2,4 VERY LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for risk of bias 2Rated down for imprecision 3Rated down for inconsistency 4Rated down for indirectness (comparator oral 5-ASA therapy was based on low-dose, not standard-dose 5-ASA) Table 14. GRADE Evidence Profile comparing rectal 5-aminosalicylates with oral 5-aminosalicylates for induction and maintenance of remission in patients with mild-moderate ulcerative proctosigmoiditis or proctitis
80
RECTAL MESALAMINE ENEMAS COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE PROCTOSIGMOIDITIS
Failure to induce remission 732 per 1,000 366 per 1,000 (256 to 534)
RR 0.50 (0.35 to 0.73)
366 fewer per 1,000 (from 198 fewer to 476 fewer)
342 (4 RCTs)
◯1 MODERATE
Failure to maintain remission 846 per 1,000 254 per 1,000
(93 to 685) RR 0.30 (0.11 to 0.81)
592 fewer per 1,000 (from 161 fewer to 753 fewer)
25 (1 RCT)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since optimal information size not met (<200 events) Table 15. GRADE Evidence Profile comparing rectal mesalamine with placebo for induction and maintenance of remission in patients with mild-moderate ulcerative proctosigmoiditis
81
RECTAL CORTICOSTEROID THERAPY COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE PROCTOSIGMOIDITIS
Failure to induce remission 802 per 1,000 585 per 1,000 (529 to 641)
RR 0.73 (0.66 to 0.80)
216 fewer per 1,000 (from 160 fewer to 273 fewer)
827 (4 RCTs)
HIGH
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
Table 16. GRADE Evidence Profile comparing rectal corticosteroids (enema or foam) with placebo for induction of remission in patients with mild-moderate ulcerative proctosigmoiditis
82
RECTAL MESALAMINE COMPARED TO RECTAL CORTICOSTEROID FOR MILD-MODERATE ULCERATIVE PROCTOSIGMOIDITS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with rectal corticosteroids
Risk with rectal mesalamine
Failure to induce remission 589 per 1,000 436 per 1,000 (359 to 530)
RR 0.74 (0.61 to 0.90)
153 fewer per 1,000 (from 59 fewer to 230 fewer)
1407 (13 RCTs)
◯1 MODERATE
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for inconsistency Table 17. GRADE Evidence Profile comparing rectal mesalamine with rectal corticosteroids for induction of remission in patients with mild-moderate ulcerative proctosigmoiditis
83
RECTAL MESALAMINE SUPPOSITORIES COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE PROCTITIS
Failure to induce remission 818 per 1,000 360 per 1,000 (278 to 458)
RR 0.44 (0.34 to 0.56)
458 fewer per 1,000 (from 360 fewer to 540 fewer)
342 (4 RCTs)
◯1 MODERATE
Failure to maintain remission 659 per 1,000 330 per 1,000
(211 to 521) RR 0.50 (0.32 to 0.79)
330 fewer per 1,000 (from 138 fewer to 448 fewer)
302 (4 RCTs)
◯◯1,2 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since optimal information size not met (<200 events) 2Rated down for risk of bias Table 18. GRADE Evidence Profile comparing rectal mesalamine suppositories with placebo for induction and maintenance of remission in patients with mild-moderate ulcerative proctitis
84
PROBIOTICS COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
Absolute risk difference № of participants (studies)
Quality of the evidence (GRADE)
Risk with mesalamine
Risk with probiotics
Failure to induce remission 254 per 1,000 315 per 1,000 (178 to 564)
RR 1.24 (0.70 to 2.22)
61 more per 1,000 (from 76 fewer to 310 more)
116 (1 RCT)
◯◯1,3 LOW
Failure to maintain remission 458 per 1,000 462 per 1,000
(385 to 558) RR 1.01 (0.84 to 1.22)
5 more per 1,000 (from 73 fewer to 101 more)
452 (2 RCTs)
◯◯1,3 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for inconsistency (both in summary estimates as well as in nature of probiotic-intervention with use of different formulations) 3Rated down for risk of bias Table 19. GRADE Evidence Profile comparing probiotics with placebo or mesalamine for induction and maintenance of remission in patients with mild-moderate ulcerative colitis
85
ADDING CURCUMIN COMPARED TO PLACEBO FOR ORAL MESALAMINE-REFRACTORY MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 854 per 1,000 598 per 1,000 (410 to 879)
RR 0.70 (0.48 to 1.03)
256 fewer per 1,000 (from 26 more to 444 fewer)
159 (3 RCTs)
◯◯◯1,2,3 VERY LOW
Failure to maintain remission 295 per 1,000 89 per 1,000
(33 to 251) RR 0.30 (0.11 to 0.85)
207 fewer per 1,000 (from 44 fewer to 263 fewer)
89 (1 RCT)
◯◯1,3 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision 2Rated down for inconsistency (both in summary estimates as well as in dose of curcumin used) 3Rated down for risk of bias Table 20. GRADE Evidence Profile comparing adding curcumin to mesalamine vs. placebo, for induction and maintenance of remission in patients with oral mesalamine-refractory mild-moderate ulcerative colitis
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FECAL MICROBIOTA TRANSPLANTATION COMPARED TO PLACEBO FOR MILD-MODERATE ULCERATIVE COLITIS
Failure to induce remission 907 per 1,000 726 per 1,000 (644 to 807)
RR 0.80 (0.71 to 0.89)
181 fewer per 1,000 (from 100 fewer to 263 fewer)
281 (4 RCTs)
◯◯1,2 LOW
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Rated down for imprecision since optimal information size not met (<200 events) 2Rated down for inconsistency (variability in intervention, with differences in route and frequency of administration, amount and source of stool) Table 21. GRADE Evidence Profile comparing fecal microbiota transplantation with placebo for induction of remission in patients with mild-moderate ulcerative colitis
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FIGURES – Forest Plots
eFigure 1. PICO#1 – Efficacy of low-, standard- and high-dose mesalamine vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
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eFigure 2. PICO#1 – Efficacy of high- and standard-dose vs. low-dose mesalamine for INDUCTION of remission in patients with mild-moderate UC.
eFigure 3. PICO#1 – Efficacy of high- vs. standard-dose mesalamine for INDUCTION of remission in patients with mild-moderate UC.
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eFigure 4. PICO#1 – Efficacy of low-, standard- and high-dose mesalamine vs. placebo for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 5. PICO#1 – Efficacy of standard-dose vs. low-dose mesalamine for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 6. PICO#1 – Efficacy of high-dose vs. standard-dose mesalamine for MAINTENANCE of remission in patients with mild-moderate UC.
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eFigure 7. PICO#1 – Tolerability of low-, standard- and high-dose mesalamine vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
eFigure 8. PICO#1 – Tolerability of low-, standard- and high-dose mesalamine vs. placebo for MAINTENANCE of remission in patients with mild-moderate UC.
92
eFigure 9. PICO#2 – Efficacy of diazo-bonded vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
eFigure 10. PICO#2 – Tolerability of diazo-bonded vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
93
eFigure 11. PICO#2 – Efficacy of diazo-bonded 5-ASA vs. placebo for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 12. PICO#2 – Efficacy of mesalamine vs. diazo-bonded 5-ASA for INDUCTION of remission in patients with mild-moderate UC (Note: Kruis 1998 studied olsalazine and all other trials studied balsalazide)
eFigure 13. PICO#2 – Tolerability of mesalamine vs. diazo-bonded 5-ASA for INDUCTION of remission in patients with mild-moderate UC (Note: Kruis 1998 studied olsalazine and all other trials studied balsalazide)
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eFigure 14. PICO#2 – Efficacy of mesalamine vs. diazo-bonded 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC
eFigure 15. PICO#2 – Tolerability of mesalamine vs. diazo-bonded 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC
eFigure 16. PICO#2 – Efficacy of sulfasalazine vs. diazo-bonded 5-ASA for INDUCTION of remission in patients with mild-moderate UC
eFigure 17. PICO#2 – Tolerability of sulfasalazine vs. diazo-bonded 5-ASA for INDUCTION of remission in patients with mild-moderate UC
95
eFigure 18. PICO#2 – Efficacy of sulfasalazine vs. diazo-bonded 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC
eFigure 19. PICO#2 – Tolerability of sulfasalazine vs. diazo-bonded 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC
96
eFigure 20. PICO#3 – Efficacy of sulfasalazine vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
eFigure 21. PICO#3 – Efficacy of sulfasalazine vs. placebo for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 22. PICO#3 – Tolerability of sulfasalazine vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
eFigure 23. PICO#3 – Tolerability of sulfasalazine vs. placebo for MAINTENANCE of remission in patients with mild-moderate UC.
97
eFigure 24. PICO#3 – Efficacy of sulfasalazine vs. mesalamine for INDUCTION of remission in patients with mild-moderate UC.
eFigure 25. PICO#3 – Tolerability of sulfasalazine vs. mesalamine for INDUCTION of remission in patients with mild-moderate UC.
eFigure 26. PICO#3 – Efficacy of sulfasalazine vs. mesalamine for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 27. PICO#3 – Tolerability of sulfasalazine vs. mesalamine for MAINTENANCE of remission in patients with mild-moderate UC.
98
eFigure 28. PICO#4 – Efficacy of oral + topical 5-ASA vs. oral 5-ASA for INDUCTION of remission in patients with mild-moderate UC.
eFigure 29. PICO#4 – Efficacy of oral + topical 5-ASA vs. oral 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC.
99
eFigure 30. PICO#5 – Efficacy of once-daily vs. multiple-times daily equivalent doses of mesalamine for INDUCTION of remission in patients with mild-moderate UC.
eFigure 31. PICO#5 – Efficacy of once-daily vs. multiple-times daily equivalent doses of mesalamine for MAINTENANCE of remission in patients with mild-moderate UC.
eFigure 32. PICO#5 – Adherence of once-daily vs. multiple-times daily equivalent doses of mesalamine in patients with mild-moderate UC.
100
eFigure 33. PICO#5 – Tolerability of once-daily vs. multiple-times daily equivalent doses of mesalamine in patients with mild-moderate UC.
101
eFigure 34. PICO#6 – Efficacy of budesonide MMX vs. placebo for INDUCTION of remission in patients with mild-moderate UC.
eFigure 35. PICO#6 – Tolerabiliy of budesonide MMX vs. placebo in patients with mild-moderate UC.
eFigure 36. PICO#6 – Efficacy of 2nd-generation corticosteroids vs. oral prednisone/prednisolone for INDUCTION of remission in patients with mild-moderate UC.
eFigure 37. PICO#6 – Risk of steroid-related adverse events with 2nd-generation corticosteroids vs. oral prednisone/prednisolone for INDUCTION of remission in patients with mild-moderate UC.
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eFigure 38. PICO#7 – Efficacy of topical 5-ASA vs. oral 5-ASA for INDUCTION of remission in patients with mild-moderate UC.
eFigure 39. PICO#7 – Efficacy of topical 5-ASA vs. oral 5-ASA for MAINTENANCE of remission in patients with mild-moderate UC.
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eFigure 40. PICO#8 – Efficacy of 5-ASA enemas vs. placebo for INDUCTION of remission in patients with mild-moderate left-sided UC.
eFigure 41. PICO#8 – Efficacy of budesonide enemas vs. placebo for INDUCTION of remission in patients with mild-moderate left-sided UC.
eFigure 42. PICO#8 – Efficacy of topical 5-ASA vs. topical steroids for INDUCTION of remission in patients with mild-moderate left-sided UC.
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eFigure 43. PICO#9 – Efficacy of 5-ASA suppositories vs. placebo for INDUCTION of remission in patients with mild-moderate ulcerative proctitis.
eFigure 44. PICO#9 – Efficacy of 5-ASA suppositories vs. placebo for MAINTENANCE of remission in patients with mild-moderate ulcerative proctitis.
105
eFigure 45. PICO#10 – Efficacy of probiotics vs. placebo for INDUCTION of remission in patients with mild-moderate ulcerative colitis.
eFigure 46. PICO#10 – Efficacy of probiotics vs. placebo for MAINTENANCE of remission in patients with mild-moderate ulcerative colitis.
eFigure 47. PICO#10 – Efficacy of probiotics vs. mesalamine for MAINTENANCE of remission in patients with mild-moderate ulcerative colitis.
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eFigure 48. PICO#11 – Efficacy of curcumin vs. placebo for INDUCTION of remission in patients with mild-moderate ulcerative colitis.
eFigure 49. PICO#12 – Efficacy of fecal microbiota transplantation vs. placebo for INDUCTION of remission in patients with mild-moderate ulcerative colitis.
eFigure 50. PICO#12 – Safety of fecal microbiota transplantation vs. placebo for INDUCTION of remission in patients with mild-moderate ulcerative colitis.