AGA Manejo CU Leve A Moderada 2019

Gastroenterology 2019;-:1–17
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American Gastroenterological Association Institute Guideline on 64
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6 the Management of Mild-to-Moderate Ulcerative Colitis 66
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8 Q8 Cynthia W. Ko,1 Siddharth Singh,2 Joseph D. Feuerstein,3 Corinna Falck-Ytter,4 68
9 Yngve Falck-Ytter,5 and Raymond K. Cross,6 on behalf of the American Gastroenterological 69
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Association Institute Clinical Guidelines Committee 71
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13 Division of Gastroenterology, University of Washington, Seattle, Washington; 2Division of Gastroenterology, University of 73
California, San Diego, La Jolla, California; 3Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth
14 Israel Deaconess Medical Center, Boston, Massachusetts; 4Division of Internal Medicine, Louis Stokes Veterans Affairs Medical 74
15 Center, Case Western Reserve University, Cleveland, Ohio; 5Division of Gastroenterology, Case Western Reserve University, 75
16 and Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio; and 6Division of Gastroenterology and Hepatology, 76
17 University of Maryland, Baltimore, Maryland 77
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T his document presents the official recommendations
of the American Gastroenterological Association
(AGA) on the management of mild-to-moderate ulcerative
elevated inflammatory markers.5 Clinicians should be aware
of these high-risk features to identify patients would may
benefit from more aggressive initial therapy or who might
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22 colitis (UC). The guideline was developed by the AGA need more rapid intensification of therapy if symptoms are 82
23 Institute’s Clinical Guidelines Committee and approved by not adequately controlled. In addition, clinicians should 83
24 the AGA Governing Board. It is accompanied by a technical avoid repeated courses of corticosteroids, even in those with 84
25 review1 that is a compilation of the clinical evidence on mild–moderate disease, and consider escalation of therapy 85
26 which these recommendations were formulated. Develop- in patients who frequently need corticosteroids for disease 86
27 ment of this guideline and the accompanying technical control. 87
28 review was fully funded by the AGA Institute without Patients with UC may have variable anatomic extent of 88
29 additional outside funding. their disease. Conventionally, patients are defined as having 89
30 UC is a chronic inflammatory bowel disease with onset extensive disease if inflammation extends proximal to the 90
31 most frequently in young adulthood. Most patients with UC splenic flexure, left-sided disease if inflammation extends 91
32 have a mild-to-moderate course characterized by periods of proximal to the rectum but not past the splenic flexure 92
33 activity or remission. More than 90% of patients with UC are (or <50 cm from the anus), and proctitis if inflammation is 93
34 Q5 treated with 5-aminosalicylates (5-ASA) shortly after dis- limited to the rectum (or <15–20 cm from the anus). Both 94
35 ease diagnosis, and most who achieve clinical remission disease severity and anatomic extent are important in 95
36 with these medications continue them for maintenance of choosing appropriate treatment. 96
37 remission.2 The minority of patients with UC require im- The mainstay of therapy for mild–moderate UC is the 97
38 munomodulators or biologic therapies for disease control.2 5-ASA class of medications, including sulfasalazine, mesal- 98
39 The severity of UC is generally classified as mild-to- amine, and diazo-bonded 5-ASA (Table 1). Sulfasalazine, the 99
40 moderate or moderate-to-severe. The definition of mild-to- oldest medication in this class, consists of 5-ASA bonded to 100
41 moderate disease activity in UC varies in clinical practice sulfapyridine. Sulfasalazine is converted to the sulfapyridine 101
42 and the medical literature. For this guideline and the and 5-ASA moieties by colonic bacteria. The 5-ASA moiety is 102
43 accompanying technical review, mild–moderate UC was believed to be the active compound for treatment of UC, 103
44 defined as patients with <4–6 bowel movements per day, while sulfapyridine is thought to contribute to adverse 104
45 mild–moderate rectal bleeding, absence of constitutional effects. Mesalamine is available in a variety of formulations 105
46 symptoms, low overall inflammatory burden, and absence of designed to deliver the active compound to different parts 106
47 features suggestive of high inflammatory activity, based of the small or large intestine. Diazo-bonded 5-ASAs, 107
48 upon Truelove and Witt’s criteria3 and the Mayo Clinic including balsalazide and olsalazine, are prodrugs converted 108
AGA SECTION
49 score.4 Although disease activity exists on a spectrum, to 5-ASA by colonic bacteria. Systemic exposure to 5-ASA is 109
50 patients in the mild–moderate category who have more similar for all oral mesalamine preparations and diazo- 110
51 frequent bowel movements, more prominent rectal bonded 5-ASAs.6 Therapeutic efficacy and safety are also 111
52 bleeding, or greater overall inflammatory burden should be 112
53 considered to have moderate disease. Patients with mild– 113
54 moderate disease activity generally are at low risk of Abbreviations used in this paper: AGA, American Gastroenterological 114
55 requiring colectomy. However, certain disease features, Association; 5-ASA, 5-aminosalicylates; CIR, controlled ileal release; FMT, 115
fecal microbiota transplantation; GRADE, Grading of Recommendations
56 even in patients who present initially with mild–moderate Assessment, Development and Evaluation; RCT, randomized controlled 116
57 disease activity, may predict an aggressive disease trial; RR, relative risk; UC, ulcerative colitis. 117
58 course.5 These include age younger than 40 years at diag- 118
59 nosis, extensive disease, severe endoscopic activity (pres- © 2018 by the AGA Institute
0016-5085/$36.00
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60 ence of deep ulcers), extra-intestinal manifestations, and https://doi.org/10.1053/j.gastro.2018.12.009 120
PGL 5.5.0 DTD YGAST62322_proof 27 December 2018 5:20 pm ce

2 Ko et al Gastroenterology Vol. -, No. -
121 Table 1.Characteristics of Available 5-Aminosalicylates and Sulfasalazine 181

122 Mesalamine Diazo-bonded 5-ASAs Sulfasalazine 182
123 183
124 Chemical structure 184
125 5-ASA Prodrug converted to 5-ASA in the colon Prodrug consisting of 5-ASA linked to 185
126 Olsalazine consists of two 5-ASA moieties sulfapyridine and 5-ASA 186
joined by an azo bond Converted to 5-ASA and sulfapyridine
127 187
Balsalazide consists of one 5-ASA moiety moieties in the colon
128 linked to an inert carrier molecule The 5-ASA moiety is believed to be the 188
129 active compound for treatment of 189
130 ulcerative colitis, while sulfapyridine is 190
131 thought to contribute to most adverse 191
132 effects 192
133 Availability 193
Delayed-release enteric-coated tablet: Olsalazine Enteric or non-enteric–coated tablets
134 pH-sensitive to allow release in distal
194
135 ileum and colon 195
136 Controlled release: delivery beginning in Balsalazide 196
137 duodenum and continuing into lower 197
138 bowel 198
139 MMX-delayed and extended delivery 199
throughout the lower bowel
140 200
Capsule containing delayed enteric-coated
141 granules
201
142 Dosage 202
143 Low dose: <2 g/d mesalamine 6.75 g balsalazide provides approximately 4 g sulfasalazine provides approximately 1.6 203
144 Standard dose: 2–3 g/d mesalamine 2.4 g 5-ASA g 5-ASA 204
145 High dose: >3 g/d mesalamine 205
146 Adverse effects 206
Rare idiosyncratic worsening of colitis, Secretory diarrhea (primarily with olsalazine) Interferes with folate metabolism
147 207
presumed hypersensitivity syndrome Rare idiosyncratic worsening of colitis, Male infertility
148 Rare: interstitial nephritis presumed hypersensitivity syndrome Rare serious cutaneous side effects, such as 208
149 Rare: interstitial nephritis Stevens-Johnson syndrome 209
150 Anemia, leukopenia, and thrombocytopenia 210
151 Pneumonitis 211
152 Hepatitis 212
153 Monitoring 213
Monitor renal function periodically Monitor renal function periodically Monitor complete blood count and liver
154 function tests periodically
214
155 Patients should take folic acid supplement 215
156 216
157 217
158 218
159 219
160 220
similar with different 5-ASA formulations.7 Therefore, patients with mild–moderate UC, some patients will not
161 221
comparability of the different commercial formulations of respond adequately to the therapies outlined here, and may
162 222
mesalamine at equivalent doses was assumed for purposes need to escalate therapy to systemic corticosteroids,
163 223
of this guideline. immunomodulators, or biologic therapies for induction and
164 224
This guideline addresses the medical management of maintenance of remission. The use of biologic therapies and
165 225
patients with mild–moderate UC, focusing on use of both immunomodulators is not specifically addressed in this
166 226
oral and topical 5-ASA medications, rectal corticosteroids, guideline.
167 227
and oral budesonide. Unless otherwise specified, we do not In the recommendations presented here and the
168 228
present separate recommendations for induction and accompanying technical review,1 estimates of the effects of
AGA SECTION
169 229
maintenance of remission, as patients who receive induction different medications are presented as the risk for failure to
170 230
therapy with 5-ASAs most commonly remain on these induce or maintain remission. Therefore, a relative risk (RR)
171 231
agents to maintain remission. The guideline first discusses <1 indicates that the agent under evaluation is more
172 232
appropriate therapy for patients with extensive disease, effective than the comparison medication or placebo for
173 233
with additional specific recommendations for patients with inducing or maintaining remission; RR >1 indicates that the
174 234
proctosigmoiditis or isolated proctitis. The guideline also agent under evaluation is less effective.
175 235
covers less-conventional therapies, including probiotics, This guideline was developed using a process described
176 236
curcumin, and fecal microbiota transplantation (FMT). elsewhere.8 Briefly, the AGA process for developing
177 237
While this guideline is intended to assist in management of clinical practice guidelines incorporates Grading of
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- 2019 AGA Section 3
241 Table 2.Grading of Recommendations Assessment, recommendations, quality of evidence, and strength of 301
Development, and Evaluation Definitions of Quality recommendations are summarized in Table 4.
242 and Certainty of the Evidence 302
243 303
Recommendation 1. In patients with extensive
244 Quality grade Definition mild–moderate UC, the AGA recommends using
304
245 either standard-dose mesalamine (2–3 g/d) or 305
246 High We are very confident that the true effect lies close
diazo-bonded 5-ASA rather than low-dose 306
to the estimate of the effect.
247 mesalamine, sulfasalazine, or no treatment. Strong 307
Moderate We are moderately confident in the effect estimate.
248 The true effect is likely to be close to the
recommendation, moderate quality evidence. 308
249 Comment: Patients already on sulfasalazine in 309
estimate of effect, but there is a possibility that
250 remission or patients with prominent arthritic
it is substantially different. 310
symptoms may reasonably choose sulfasalazine 2–4
251 Low Our confidence in the estimate is limited. The true
g/d if alternatives are cost-prohibitive, albeit with 311
252 effect may be substantially different from the
higher rate of intolerance. 312
253 estimate of effect. 313
Very low We have very little confidence in the effect
254 estimate. The true effect is likely to be
314
255 substantially different from the estimate of The AGA recommends treating patients with extensive 315
256 effect. mild–moderate UC with either standard-dose mesalamine 316
257 Evidence gap Available evidence is insufficient to determine true or diazo-bonded 5-ASA. Eighteen randomized controlled 317
258 effect. trials (RCTs) comparing different doses of mesalamine or 318
259 placebo were identified and reviewed. For purposes of this 319
260 guideline and the technical review, low-dose mesalamine 320
261 was defined as a total daily dose <2 g, standard dose as 2–3 321
262 Recommendations Assessment, Development and Evalua- g/d, and high dose as >3 g/d. High-dose,4,11–15 standard- 322
263 tion (GRADE) methodology9 and best practices as outlined dose,11,13,14,16–19 and low-dose mesalamine4,11,16,18 were all 323
264 by the Institute of Medicine.10 GRADE methodology was superior to placebo for induction of remission (RR, 0.75; 324
265 used to prepare the background information for the 95% confidence interval [CI], 0.66–0.86 for high dose; RR, 325
266 guideline and the accompanying technical review. Optimal 0.84; 95% CI, 0.78–0.91 for standard dose; RR, 0.88; 95% CI, 326
267 understanding of the guideline will be enhanced by 0.82–0.94 for low dose), and all doses were well tolerated. 327
268 reading the applicable portions of the technical review. Both high-dose4, 11,20–23 and standard-dose11,15,16,18,20–24 328
269 The guideline panel and the authors of the technical mesalamine were superior to low-dose mesalamine for in- 329
270 review met face to face on March 4, 2018 to discuss duction of remission (RR, 0.81; 95% CI, 0.71–0.92 for high 330
271 the findings from the technical review. The guideline dose; RR, 0.88; 95% CI, 0.79–0.99 for standard dose), with 331
272 authors subsequently formulated the recommendations. a trend favoring a modest benefit of high-dose over 332
273 Although the quality of evidence (Table 2) was a key standard-dose mesalamine (RR, 0.94; 95% CI, 0.88– 333
274 factor in determining the strength of the recommendations 1.01).11,13–15,20–23,25–28 For maintenance of remission, both 334
275 (Table 3), the panel also considered the balance standard-dose29,30 and low-dose mesalamine31–33 were 335
276 between benefit and harm of interventions, patients’ superior to placebo (RR, 0.55; 95% CI, 0.43–0.70 for stan- 336
277 values and preferences, and resource utilization. The dard dose; RR, 0.63; 95% CI, 0.51–0.78 for low dose), and 337
278 338
279 339
280 Table 3.Grading of Recommendations Assessment, Development, and Evaluation Definitions on Strength of 340
281 Recommendation and Guide to Interpretation 341
282 342
283 Strength of Wording in 343
284 recommendation the guideline For the patient For the clinician 344
285 Strong “The AGA recommends.” Most individuals in this situation Most individuals should receive the recommended
345
286 would want the recommended course of action. Formal decision aids are not 346
287 course and only a small likely to be needed to help individuals make 347
288 proportion would not. decisions consistent with their values and 348
AGA SECTION
289 preferences. 349

290 Conditional “The AGA suggests.” The majority of individuals in this Different choices would be appropriate for different 350
situation would want the patients. Decision aids may be useful in helping
291 351
suggested course, but many individuals in making decisions consistent with
292 would not. their values and preferences. Clinicians should 352
293 expect to spend more time with patients when 353
294 working towards a decision. 354
295 No recommendation “The AGA makes — The confidence in the effect estimate is so low that 355
296 no recommendation.” any effect estimate is speculative at this time. 356
297 357
298 358
299 359
300 360

361 Table 4.Summary of Recommendations of the American Gastroenterological Association Clinical Guidelines Committee for 421
the Management of Mild-to-Moderate Ulcerative Colitis
362 422
363 Strength of Quality of 423
364 Recommendations recommendation evidence 424
365 425
366 1. In patients with extensive mild–moderate UC, the AGA recommends using either Strong Moderate 426
367 standard-dose mesalamine (2–3 g/d) or diazo-bonded 5-ASA rather than low-dose 427
mesalamine, sulfasalazine, or no treatment.
368 Comment: Patients already on sulfasalazine in remission or patients with prominent arthritic
428
369 symptoms may reasonably choose sulfasalazine 2–4 g/d if alternatives are cost- 429
370 prohibitive, albeit with higher rate of intolerance 430
371 2. In patients with extensive or left-sided mild–moderate UC, the AGA suggests adding rectal Conditional Moderate 431
372 mesalamine to oral 5-ASA. 432
373 3. In patients with mild–moderate UC with suboptimal response to standard-dose Conditional Moderate (induction 433
mesalamine or diazo-bonded 5-ASA or with moderate disease activity, the AGA suggests of remission)
374 434
using high-dose mesalamine (>3 g/d) with rectal mesalamine. Low (maintenance
375 of remission)
435
376 4. In patients with mild–moderate UC being treated with oral mesalamine, the AGA suggests Conditional Moderate 436
377 using once-daily dosing rather than multiple times per day dosing. 437
378 5. In patients with mild–moderate UC, the AGA suggests using standard-dose oral Conditional Low 438
379 mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX or controlled ileal 439
380 release budesonide for induction of remission. 440
6. In patients with left-sided mild–moderate ulcerative proctosigmoiditis or proctitis, the AGA Conditional Very low
381 441
suggests using mesalamine enemas (or suppositories) rather than oral mesalamine.
382 Comment: patients who place a higher value on convenience of oral medication 442
383 administration and a lower value on effectiveness could reasonably choose oral 443
384 mesalamine. 444
385 7. In patients with mild–moderate ulcerative proctosigmoiditis who choose rectal therapy Conditional Moderate 445
386 over oral therapy, the AGA suggests using mesalamine enemas rather than rectal 446
387 corticosteroids. 447
Comment: Patients who place a higher value on avoiding difficulties associated with
388 mesalamine enemas and a lower value on effectiveness may reasonably select rectal
448
389 corticosteroid foam preparations. 449
390 8. In patients with mild–moderate ulcerative proctitis who choose rectal therapy over oral Strong Moderate 450
391 therapy, the AGA recommends using mesalamine suppositories. 451
392 9. In patients with mild–moderate ulcerative proctosigmoiditis or proctitis being treated with Conditional Low 452
393 rectal therapy who are intolerant of or refractory to mesalamine suppositories, the AGA 453
suggests using rectal corticosteroid therapy rather than no therapy for induction of
394 454
remission.
395 10. In patients with mild–moderate UC refractory to optimized oral and rectal 5-ASA, Conditional Low
455
396 regardless of disease extent, the AGA suggests adding either oral prednisone or 456
397 budesonide MMX. 457
398 11. In patients with mild–moderate UC, the AGA makes no recommendation for use of No recommendation Knowledge gap 458
399 probiotics. 459
400 12. In patients with mild–moderate UC despite 5-ASA therapy, the AGA makes no No recommendation Knowledge gap 460
recommendation for use of curcumin.
401 461
13. In patients with mild–moderate UC without Clostridium difficile infection, the AGA No recommendation Knowledge gap
402 recommends fecal microbiota transplantation be performed only in the context of a for treatment of UC 462
403 clinical trial. 463
404 464
405 465
406 466
407 467
408 standard-dose was superior to low-dose mesalamine34–37 tolerated than both placebo and balsalazide due to the 468
adverse effect of watery diarrhea.1 There was also a
AGA SECTION
409 (RR, 0.63; 95% CI, 0.55–0.78). No benefit of high-dose 469

410 over standard-dose mesalamine was seen for maintenance trend toward superiority of diazo-bonded 5-ASA over 470
411 of remission38,39 (RR, 0.93; 95% CI, 0.71–1.17). standard-dose mesalamine for induction of remission48–52 471
412 Six RCTs comparing diazo-bonded 5-ASA with placebo (RR, 0.81; 95% CI, 0.60–1.08). Diazo-bonded 5-ASA was 472
413 for induction40–45 and 2 trials of olsalazine46,47 for mainte- more effective than mesalamine for maintenance of 473
414 nance of remission were identified. No trials of balsalazide remission53–55 (RR, 0.69; 95% CI, 0.51–0.98), though only 474
415 for maintenance of remission were found. Diazo-bonded low-dose mesalamine was used for comparison in these 475
416 5-ASA was significantly better than placebo for both trials. Rates of treatment discontinuation were higher for 476
417 induction (RR, 0.86; 95% CI, 0.76–0.98) and was numeri- olsalazine than placebo, but not for balsalazide vs placebo. 477
418 cally, but not statistically, better for maintenance of remis- Evidence for sulfasalazine comes from 2 RCTs conducted 478
419 sion (RR, 0.71; 95% CI, 0.41–1.21). Olsalazine was less well in the 1960s. In these studies, sulfasalazine was given at 479
420 480

481 doses of 2–6 g/d and was more effective than placebo for remission. There may be a small benefit for high-dose 541
482 induction of remission56,57 (RR, 0.62; 95% CI, 0.45–0.87). mesalamine over standard-dose mesalamine for induction 542
483 There was large heterogeneity in the effect estimate, with a of remission, but not necessarily maintenance. Balsalazide is 543
484 larger effect size observed in the trial using doses of 4–6 g/d. the better-tolerated diazo-bonded 5-ASA, with similar 544
485 Sulfasalazine 2 g/d was more effective than placebo for effectiveness to standard-dose mesalamine for induction 545
486 maintenance of remission58–61 (RR, 0.45; 95% CI, 0.23–0.89). and better efficacy for maintenance. Therefore, either 546
487 However, sulfasalazine was not well tolerated, with a high standard-dose mesalamine or balsalazide are appropriate 547
488 rate of treatment discontinuation in the induction trials (RR for treatment of extensive mild–moderate UC. Sulfasalazine 548
489 for treatment discontinuation, 5.14; 95% CI, 0.95–27.93). In is potentially an acceptable alternative in patients who can 549
490 trials of maintenance therapy enrolling patients who entered tolerate it or in patients with prominent arthritic symptoms. 550
491 remission on sulfasalazine, tolerability was better with The overall quality of evidence for this recommendation 551
492 modestly increased rates of treatment discontinuation was moderate for both induction and maintenance of 552
493 compared to placebo58–61 (RR, 2.22; 95% CI, 0.67–7.35). remission (Tables 3–7 in accompanying technical review). 553
494 Pooled analysis of 4 trials comparing sulfasalazine to Evidence for high or standard-dose mesalamine vs placebo 554
495 standard-dose mesalamine strongly suggested superiority of or low-dose mesalamine was rated as high quality; evidence 555
496 mesalamine21,24,62,63 (RR, 1.27; 95% CI, 0.94–1.73). For for use of high-dose over standard-dose mesalamine for 556
497 maintenance of remission, pooled estimates from 6 RCTs, induction was rated as moderate quality. The quality of 557
498 most of which used low-dose mesalamine, showed that evidence for diazo-bonded 5-ASA vs placebo for induction of 558
499 sulfasalazine was not statistically inferior to mesalamine64–69 remission was rated high. However, the evidence for 559
500 (RR, 1.13; 95% CI, 0.91–1.40). Like mesalamine, diazo- maintenance of remission was low quality due to impreci- 560
501 bonded 5-ASA was more effective than sulfasalazine for sion and indirectness. In particular, no trials of balsalazide 561
502 inducing remission70–77 (RR, 0.77; 95% CI, 0.61–0.96) with vs placebo for maintenance of remission were identified. 562
503 similar effectiveness for maintenance of remission76,78–82 Only low-quality evidence supported a benefit of diazo- 563
504 (RR, 1.07; 95% CI, 0.98–1.16). Overall, mesalamine and bonded 5-ASA over standard-dose mesalamine for induc- 564
505 diazo-bonded 5-ASA were better tolerated than sulfasalazine tion and maintenance of remission because the maintenance 565
506 in the induction but not the maintenance trials. trials used low-dose, rather than standard-dose, mesal- 566
507 Systemic exposure to 5-ASA is similar for all oral amine. Evidence supporting use of sulfasalazine over pla- 567
508 mesalamine preparations and diazo-bonded 5-ASA.6 Mesal- cebo was rated down due to imprecision for induction, and 568
509 amine and balsalazide are generally well tolerated without due to imprecision and indirectness for maintenance. 569
510 significant adverse events, except for the rare occurrence of 570
interstitial nephritis (Table 1). Olsalazine is generally less Recommendation 2. In patients with extensive or
511 left-sided mild–moderate ulcerative colitis, the AGA 571
512 well tolerated than either mesalamine or balsalazide, with 572
up to a 20% risk of secretory diarrhea necessitating treat- suggests adding rectal mesalamine to oral 5-ASA.
513 Conditional recommendation, moderate quality 573
514 ment discontinuation. Although many different preparations evidence. 574
515 of mesalamine are commercially available, there is little 575
516 evidence to suggest differences in efficacy between them.7 576
517 Therefore, we do not recommend switching between The AGA suggests adding rectal mesalamine to oral 577
518 mesalamine preparations in search of more effective treat- 5-ASA therapy for patients with extensive mild–moderate 578
519 ment. Balsalazide is the preferred diazo-bonded 5-ASA due UC. Four RCTs comparing combined oral and topical 579
520 to its better tolerability. 5-ASA vs oral sulfasalazine or standard-dose mesalamine 580
521 Conversely, sulfasalazine is often poorly tolerated due to for induction of remission were identified. Combination 581
522 side effects, such as headache, nausea, diarrhea, and rash therapy was significantly more effective for induction of 582
523 (Table 1). Patients often need to start at lower-dose sulfa- remission86–89 (RR, 0.68; 95% CI, 0.49–0.94), and was 583
524 salazine with gradual dose escalation as tolerated. In addi- superior to oral 5-ASA alone for maintenance of remission 584
525 tion, sulfasalazine interferes with folic acid metabolism, and in 2 RCTs90,91 (RR, 0.45; 95% CI, 0.20–0.97). In the main- 585
526 patients are recommended to take folate supplementation. tenance trials, enemas were used twice per week or for 586
527 Rare but serious cutaneous side effects, allergic reactions, 1 week per month. Both oral and topical mesalamine were 587
528 hepatitis, and hematologic toxicity are also possible. well tolerated. 588
AGA SECTION
529 Because of these side effects, laboratory monitoring of Combined oral and rectal therapy may allow a higher 589
530 complete blood counts and liver function tests is needed. effective dose of 5-ASA to be delivered to the involved area 590
531 Overall, sulfasalazine may be more difficult to incorporate of the colon. The strategy of combining oral and topical 591
532 routinely into clinical practice because of its adverse effects therapy allows optimization of 5-ASA regimens to achieve 592
533 and need for laboratory monitoring. However, sulfasalazine higher rates of induction and maintenance of remission, 593
534 is commonly prescribed for rheumatologic disorders, potentially avoiding escalation of therapy to corticosteroids 594
535 including spondyloarthropathies, rheumatoid arthritis, and or immunosuppression. A potential drawback to a combined 595
536 psoriatic arthritis,83–85 and patients with concomitant strategy is low patient acceptance of topical therapy and 596
537 arthritic symptoms may benefit from its use. suboptimal adherence. Patients may prefer to try oral 597
538 Overall, standard-dose mesalamine and diazo-bonded therapy first, with addition of rectal therapy in the event of 598
539 5-ASA are effective for both induction and maintenance of inadequate response. Although trials did not compare 599
540 600

601 optimized combination therapy with oral and rectal 5-ASA combined oral and rectal therapy will effectively deliver a 661
602 vs corticosteroids and/or immunosuppressive therapy in higher dose of mesalamine to the involved area of colon and 662
603 the subset of patients with persistent mild–moderate dis- optimize use of 5-ASA–based therapy before escalating 663
604 ease activity, combination therapy may be able to salvage treatment. 664
605 some patients with inadequate response to oral 5-ASA, and 665
may be more acceptable to patients who wish to avoid Recommendation 4. In patients with mild–moderate
606 UC being treated with oral mesalamine, the AGA
666
607 corticosteroids or immunosuppression.92 667
The overall evidence for this recommendation was rated suggests using once-daily dosing rather than
608 multiple times per day dosing. Conditional 668
609 as moderate quality. The event rates in both the induction recommendation, moderate quality evidence. 669
610 and maintenance trials were low, leading to imprecision. In 670
611 the maintenance studies, the oral mesalamine groups 671
612 received low-dose mesalamine, but the oral and rectal The AGA suggests using once-daily dosing rather than 672
613 treatment groups received >2 g mesalamine in total, leading multiple times per day dosing for patients with mild– 673
614 to indirectness because of differences in the total doses of moderate UC being treated with oral mesalamine. In 674
615 medications received. 4 RCTs comparing equivalent doses of mesalamine admin- 675
616 istered once daily vs multiple times daily, there was no 676
Recommendation 3. In patients with mild–moderate significant difference in the rate of induction of remis-
617 UC with suboptimal response to standard-dose
677
618 sion13,14,94,95 (RR, 0.96; 95% CI, 0.85–1.08), while similar 678
mesalamine or diazo-bonded 5-ASA or with rates of maintenance of remission were seen in 11 trials
619 moderate disease activity, the AGA suggests using 679
620 high-dose mesalamine (>3 g/d) with rectal comparing once or multiple times daily dosing34,36,96–104 680
621 mesalamine. Conditional recommendation, (RR, 0.96; 95% CI, 0.85–1.07). Within these clinical trials, 681
622 moderate-quality evidence [induction of remission], adherence to the different dosing schedules, defined as 682
623 low-quality evidence (maintenance of remission). taking >80% of recommended doses, was similar (pooled 683
624 adherence 92.4% with once-daily vs 93.6% with multiple 684
625 daily doses). However, medication adherence in clinical 685
The AGA suggests using combined high-dose oral trials is typically better than seen in clinical practice. A
626 686
mesalamine with rectal 5-ASA in patients with suboptimal meta-analysis of observational studies in patients with
627 687
response to standard-dose mesalamine or diazo-bonded various chronic diseases demonstrated better adherence
628 688
5-ASA or in patients with moderate disease activity, as with once-daily dosing of medications compared to more
629 689
630
defined above. High-dose oral mesalamine may have a complex dosing regimens.105 With maintenance treatment, 690
modest benefit over standard-dose for induction of non-adherence to mesalamine is common and is associated
631 691
remission11,13–15,20–23,25–28 (RR, 0.94; 95% CI, 0.88–1.01), with higher risk of disease relapse.106–108 Because clinical
632 692
and is similar for maintenance of remission38,39 (RR, 0.93; effectiveness is similar with different dosing schemes, use of
633 693
95% CI, 0.73–1.17). Escalating to high-dose over standard- once-daily dosing will likely improve adherence, allow pa-
634 694
dose mesalamine may have a modest benefit for achieving tients to achieve a higher daily dose of mesalamine, and
635 695
and maintaining remission. As discussed in Recommenda- improve overall disease control.
636 696
tion 2, addition of rectal therapy may provide some addi- This conditional recommendation is intended to apply to
637 697
tional benefit over oral therapy alone, although some all available formulations of mesalamine, as there are not
638 698
patients prefer to avoid rectal therapy.92,93 Optimization of demonstrable differences in efficacy between the different
639 699
640
5-ASA therapy by using high-dose oral therapy combined mesalamine products.7 With formulations that require a 700
with rectal therapy may allow some patients to avoid cor- large daily pill burden, taking the total recommended daily
641 701
ticosteroids or immunosuppression. dose at one time may be challenging for patients; with such
642 702
If patients are experiencing progressively worsening formulations, it is reasonable to simplify the recommended
643 703
symptoms and increasing disease severity (eg, extra- regimen into as few doses per day to maintain adherence.
644 704
intestinal manifestations or constitutional symptoms such Comparative studies of diazo-bonded 5-ASA or sulfasalazine
645 705
as weight loss or fevers), escalation to high-dose oral with different dosing schemes have not been conducted, so
646 706
mesalamine with rectal therapy may not be effective. These the panel did not make specific recommendations for these
647 707
patients should be considered for use of systemic cortico- medications.
648 708
AGA SECTION
steroids, biologic therapies, or immunomodulators to induce The quality of evidence supporting this recommendation
649 709
disease remission. Continuing 5-ASA–based therapy in these was rated as moderate quality (Table 9 in accompanying
650 710
patients may delay more effective therapy and place technical review). Evidence was rated down due to impre-
651 711
patients at risk for worsening disease and complications. cision with wide CIs for the effect estimates.
652 712
The overall quality of evidence was rated as moderate
653 713
for induction of remission and low for maintenance. Evi- Recommendation 5. In patients with mild–moderate
654 714
dence was rated down for imprecision as confidence UC, the AGA suggests using standard-dose oral
655 mesalamine or diazo-bonded 5-ASA, rather than 715
intervals for the effect estimates contained the possibility of
656 budesonide MMX or controlled ileal-release 716
no effect. Because no trials of high-dose oral and rectal
657 budesonide for induction of remission. (Conditional 717
mesalamine were identified, the evidence for this recom-
658 recommendation, low quality of evidence). 718
mendation was considered indirect. However, as mentioned,
659 719
660 720

721 The AGA suggests using standard-dose oral mesalamine The AGA suggests using mesalamine enemas (or sup- 781
722 or diazo-bonded 5-ASA over budesonide preparations for positories) rather than oral mesalamine in patients with 782
723 induction of remission. Budesonide is a high-potency corti- mild–moderate ulcerative proctosigmoiditis or proctitis. 783
724 costeroid with low systemic activity due to first pass Pooled analysis of 4 RCTs showed a trend favoring rectal 784
725 metabolism by the liver. Two oral preparations of budeso- mesalamine over oral mesalamine for induction88,112–114 785
726 nide are currently available. Budesonide MMX is designed (RR, 0.43; 95% CI, 0.14–1.31), but with considerable het- 786
727 for release throughout the colon and is approved by the US erogeneity. After excluding 1 trial comparing high-dose 787
728 Food and Drug Administration for treatment of UC, while MMX-release mesalamine vs mesalamine enemas, topical 788
729 controlled ileal release (CIR) budesonide is primarily 5-ASA was significantly more effective than oral therapy 789
730 released in the distal ileum and right colon and has not been (RR, 0.28; 95% CI, 0.14–0.56). For maintenance of remis- 790
731 specifically approved for UC. Evidence for use of CIR- sion, pooled effect estimates from 3 single-blinded trials 791
732 budesonide was derived from a 4-arm RCT comparing showed a trend for increased effectiveness of topical 5-ASA 792
733 different doses of budesonide MMX to placebo, in which vs oral therapy115–117 (RR, 0.69; 95% CI, 0.41–1.17). 793
734 CIR-budesonide was used as an active comparator.19 There In these studies, oral therapy consisted of sulfasalazine 794
735 are few long-term efficacy or safety data for use of bude- 2 g/d or low-dose mesalamine, while topical 5-ASA con- 795
736 sonide for maintenance of remission and, therefore, bude- sisted of mesalamine enemas 4 g 2–3 times per week or 796
737 sonide is unsuitable for maintenance therapy, given the 1 week per month. 797
738 potential for corticosteroid-related adverse effects. Studies of topical mesalamines for UC have used varying 798
739 In pooled analysis of 3 RCTs, budesonide MMX 9 mg/ definitions of left-sided disease. Some have defined left- 799
740 d was more effective than placebo in inducing remis- sided disease as inflammation extending up to the splenic 800
741 sion19,109,110 (RR, 0.88; 95% CI, 0.83–0.94). In 1 RCT, CIR- flexure, while others have used a definition of inflammation 801
742 budesonide was modestly more effective than placebo for extending <50 cm from the anus. However, enema prepa- 802
743 this same indication110 (RR, 0.93; 95% CI, 0.87–0.99). The rations are unlikely to reach proximal to the sigmoid colon. 803
744 4-arm CORE-I trial compared budesonide MMX 6 mg or Patients with inflammation extending into the descending 804
745 9 mg daily, mesalamine 2.4 g daily, and placebo, finding no colon may be more appropriately treated with combined 805
746 significant difference between budesonide MMX 9 mg/d and oral and topical therapy, as discussed in Recommendation 2. 806
747 mesalamine in inducing remission19 (RR, 0.94; 95% CI, Clinicians recognize that many patients prefer oral over 807
748 0.85–1.04) with similar tolerability. A separate RCT showed topical therapy, and that adherence to rectal therapy may be 808
749 CIR-budesonide to be less effective than high-dose mesal- inadequate. An additional limitation of rectal therapy is that 809
750 amine for inducing remission111 (RR, 1.34; 95% CI, 1.09– patients with active disease may have difficulty retaining 810
751 1.64) with higher discontinuation rates. In the CORE-II trial, enemas adequately due to discomfort and urgency. Given 811
752 budesonide MMX and CIR-budesonide were similarly these limitations and the uncertainty in the effect estimates, 812
753 effective in inducing remission110 (RR, 0.95; 95% CI, 0.86– patients with mild–moderate ulcerative proctitis or proc- 813
754 1.04) with comparable tolerability. Overall, the budesonide tosigmoiditis who place higher value on convenience of oral 814
755 preparations are not superior to mesalamine for induction medication administration may reasonably choose oral 815
756 of remission. The lack of superiority over 5-ASA for induc- 5-ASA over rectal therapy. Some patients with left-sided UC 816
757 tion of remission, and the lack of long-term efficacy and may choose to use combined oral and rectal therapy, as 817
758 safety data for maintenance of remission with budesonide, outlined in Recommendation 2. 818
759 make oral 5-ASAs the preferred treatment for most patients The overall quality of evidence was rated very low due 819
760 with mild–moderate UC. to high risk of bias and imprecision with wide CIs crossing 1 820
761 The quality of evidence for budesonide MMX vs placebo (Table 14 in accompanying technical review). Evidence for 821
762 was moderate and was rated down for imprecision due to induction therapy was also rated down for inconsistency. 822
763 low event rates. Evidence for CIR-budesonide vs placebo Trials for maintenance therapy were rated down for indi- 823
764 and for budesonide MMX vs mesalamine was rated as low rectness as the oral comparator was low-dose and not 824
765 quality due to imprecision and high risk of bias in the standard-dose 5-ASA. 825
766 available studies. Evidence comparing CIR-budesonide to 826
mesalamine was rated as moderate and was rated down due Recommendation 7. In patients with mild–moderate
767 ulcerative proctosigmoiditis who choose rectal
827
768 to low event rates (Tables 10 and 11 in accompanying 828
therapy over oral therapy, the AGA suggests using
AGA SECTION
769 technical review). 829

mesalamine enemas rather than rectal
770 corticosteroids. Conditional recommendation, 830
Recommendation 6. In patients with mild–moderate
771 ulcerative proctosigmoiditis or proctitis, the AGA
moderate-quality evidence. 831
772 Comment: Patients who place a higher value on avoiding 832
suggests using mesalamine enemas (or suppositories) difficulties associated with mesalamine enemas and a
773 rather than oral mesalamine. Conditional 833
lower value on effectiveness may reasonably select
774 recommendation, very-low-quality evidence. rectal corticosteroid foam preparations. 834
775 Comment: Patients who place a higher value on 835
776 convenience of oral medication administration and a 836
lower value on effectiveness could reasonably
777 If patients with ulcerative proctosigmoiditis are being 837
choose oral mesalamine.
778 treated with rectal therapy, the AGA suggests using 838
779 839
780 840

841 mesalamine enemas rather than rectal corticosteroids. mesalamine suppositories (1–1.5 g/d) are more effective 901
842 Pooled results from 4 RCTs showed that mesalamine than placebo in inducing remission (RR, 0.44; 95% CI, 902
843 enemas (4 g nightly) are more effective than placebo for 0.34–0.56).104,118,119,140 Maintenance therapy with mesal- 903
844 induction of remission118–121 (RR, 0.50; 95% CI, 0.35–0.73). amine suppositories (0.5–1 g administered once per day to 904
845 Only 1 small study of mesalamine enemas 1 g/d for main- 3 times per week) is also superior to placebo (RR, 0.50; 95% 905
846 tenance of remission was identified, showing superiority to CI, 0.32–0.79).87,90,115,141 Mesalamine suppositories are 906
847 placebo122 (RR, 0.30; 95% CI, 0.11–0.81). Rectal cortico- generally well tolerated, with few treatment-related adverse 907
848 steroid therapy is also effective for inducing remission, with effects and better retention than enemas. 908
849 a pooled RR, comparing rectal corticosteroids with placebo No RCTs or cohort studies of corticosteroid supposi- 909
850 of 0.73 (95% CI, 0.66–0.80).123–125 All the trials used rectal tories for management of ulcerative proctitis were identi- 910
851 budesonide; 2 used foam preparations, and 1 used enemas. fied. Benefit may be indirectly inferred from studies of 911
852 Meta-analysis of 13 trials comparing rectal 5-ASA corticosteroid foams or enemas in patients with proctitis 912
853 and rectal corticosteroids shows that topical 5-ASA and left-sided colitis, although the quality of evidence is low. 913
854 (enemas 1–4 g/d or suppositories 1 g/d) is superior to In addition, rectal corticosteroids have not been studied for 914
855 topical corticosteroids for inducing remission (RR, 0.74; 95% maintenance of remission in ulcerative proctitis. Given 915
856 CI, 0.61–0.90).126–138 The topical corticosteroids studied in concerns about long-term safety and effectiveness of corti- 916
857 these RCTs included hydrocortisone, prednisolone, or bude- costeroids for this indication, use of mesalamine supposi- 917
858 sonide enemas, and hydrocortisone or beclomethasone foam tories is preferred for treatment of mild–moderate 918
859 preparations. No head-to-head trials comparing budesonide ulcerative proctitis. 919
860 foam to rectal 5-ASA were identified. Similar effects were The quality of evidence for mesalamine suppositories for 920
861 seen when limiting the analysis to standard-dose 5-ASA induction of remission was rated as moderate, and was 921
862 enemas (4 g/d)129,131,133,138 (RR, 0.39; 95% CI, 0.19–0.82). rated down for imprecision due to low event rates in the 922
863 No trials of maintenance rectal corticosteroids were identified, available studies (Table 18 in accompanying technical 923
864 and their long-term effectiveness and safety are unknown. review). The evidence for mesalamine suppositories for 924
865 Overall, rectal 5-ASA is superior to rectal corticosteroids maintenance of remission was rated as low quality due to 925
866 for induction of remission, and both are superior to placebo. imprecision and risk of bias. 926
867 Given potential safety concerns with long-term rectal cor- 927
ticosteroids and superiority of rectal 5-ASA for inducing Recommendation 9. In patients with mild–moderate
868 ulcerative proctosigmoiditis or proctitis being treated
928
869 remission, topical 5-ASAs are preferred. In general, rectal 929
5-ASA and corticosteroids are both well tolerated. However, with rectal therapy who are intolerant of or
870 refractory to mesalamine suppositories, the AGA 930
871 some patients, particularly those with active disease, expe- suggests using rectal corticosteroid therapy rather 931
872 rience discomfort with enemas or are unable to retain them than no therapy for induction of remission. 932
873 adequately. Patients may prefer corticosteroid foam prepa- Conditional recommendation, low-quality evidence. 933
874 rations over enemas because of ease of delivery, better 934
875 tolerability and improved retention, and foam and enema 935
preparations of the same medication have similar effi- The AGA suggests using rectal corticosteroid therapy in
876 patients with ulcerative proctitis who are refractory to or 936
877 cacy.136,139 Thus, patients on rectal therapy who place a 937
higher value on ease and tolerance of medication adminis- intolerant of mesalamine suppositories. Although there are
878 no RCTs of corticosteroid suppositories in this population, 938
879 tration may reasonably choose corticosteroid foam prepa- 939
rations over mesalamine enemas. indirect evidence from patients with ulcerative procto-
880 sigmoiditis suggests a benefit of rectal corticosteroids, as 940
881 The quality of evidence comparing rectal 5-ASA to pla- 941
cebo for induction was moderate due to imprecision from noted.123–125 Additionally, some patients with prominent
882 proctitis symptoms may tolerate a foam preparation with 942
883 low event rates, while evidence for rectal corticosteroids vs 943
placebo for induction was rated as high (Tables 15–17 in less discomfort and improved retention compared to a
884 suppository. Therefore, a trial of a rectal corticosteroid is 944
885 accompanying technical review). The evidence supporting 945
rectal 5-ASA over corticosteroids for induction was mod- reasonable for patients with inadequate response or toler-
886 ance to mesalamine suppositories. Patients with refractory 946
887 erate, and was rated down for heterogeneity in the effect 947
size. The evidence for maintenance rectal 5-ASA was rated symptoms could also be considered for oral 5-ASAs or
888 systemic corticosteroids. 948
AGA SECTION
889 as low quality because only 1 small study was available. 949
The overall quality of evidence for this recommendation
890 was low, and was rated down for indirectness because trials 950
891 ulcerative proctitis who choose rectal therapy over were not performed specifically in ulcerative proctitis 951
892 oral therapy, the AGA recommends using patients. 952
893 mesalamine suppositories. Strong recommendation, 953
894 moderate-quality evidence. 954
895 UC refractory to optimized oral and rectal 5-ASA, 955
896 regardless of disease extent, the AGA suggests 956
897 The AGA recommends using mesalamine suppositories 957
adding either oral prednisone or budesonide MMX.
898 in patients with mild–moderate ulcerative proctitis who opt Conditional recommendation, low-quality evidence. 958
899 for rectal therapy. Pooled analysis of 4 RCTs showed that 959
900 960

961 The AGA suggests adding either oral prednisone or (RR, 0.88; 95% CI, 0.69–1.12), with considerable heteroge- 1021
962 budesonide MMX in patients with symptoms refractory to neity. Notably, these studies used several different probiotic 1022
963 optimized 5-ASA therapy. A single RCT in patients with formulations, including Bifidobacterium species, Lactoba- 1023
964 mild–moderate disease activity despite 5-ASA therapy found cillus acidophilus, VSL #3, and Escherichia coli Nissle 1917. 1024
965 that adding budesonide MMX to 5-ASA was only modestly Only 1 single small trial compared a probiotic (E coli Nissle 1025
966 more effective than placebo with 5-ASA for induction of 1917) vs standard-dose mesalamine for induction, finding 1026
967 remission142 (RR, 0.95; 95% CI, 0.89–1.00). No trials no significant difference in remission rates154 (RR, 1.24; 1027
968 directly comparing budesonide MMX with systemic corti- 95% CI, 0.70–2.22). There was no difference in rates of 1028
969 costeroids such as prednisone were identified. We reviewed maintaining remission in 2 RCTs comparing probiotics to 1029
970 3 studies comparing second-generation corticosteroids placebo155,156 (RR, 0.82; 95% CI, 0.63–1.06) or in 2 RCTs 1030
971 (CIR-budesonide, beclomethasone, and fluticasone) to comparing probiotics and mesalamine157,158 (RR, 1.01; 95% 1031
972 oral prednisone or prednisolone for induction of CI, 0.84–1.22). 1032
973 remission.143–145 Pooled results from these 3 trials showed Although probiotics are popular among patients with UC, 1033
974 no significant difference for inducing remission (RR, 1.04; their benefit for either inducing or maintaining remission is 1034
975 95% CI, 0.96–1.13). Rates of steroid-related adverse events unclear. In general, probiotics are well-tolerated with low 1035
976 were significantly lower with second-generation cortico- rates of adverse effects. However, if they are used instead of 1036
977 steroids (RR, 0.32; 95% CI, 0.16–0.64). Thus, the evidence other proven therapy, patients are at risk for progressive 1037
978 for comparable efficacy of budesonide MMX and systemic symptoms and disease complications. Thus, given their lack 1038
979 corticosteroids is indirect and in large part inferred from of proven efficacy, probiotics should not be used instead of 1039
980 studies of other second-generation corticosteroids. therapies known to be effective. The effectiveness of pro- 1040
981 Patients may fail to achieve clinical remission despite biotics added on to proven therapies, such as oral or rectal 1041
982 optimized use of 5-ASA therapy, as outlined in the preceding 5-ASA is unknown. 1042
983 recommendations. Management of these patients requires The identified RCTs were inconsistent in studying several 1043
984 escalation of therapy, most commonly consideration of a different probiotic formulations and with heterogeneous re- 1044
985 course of corticosteroids to achieve disease control. sults. Additional research in this area is needed to identify 1045
986 Some patients with high-risk features as outlined in the patient populations for whom probiotics might be beneficial, 1046
987 introduction may also need earlier consideration of corti- to identify specific bacterial strains with the greatest thera- 1047
988 costeroids. Second-generation corticosteroids and oral peutic potential, and to determine appropriate doses. 1048
989 prednisone appear to be equally effective for induction of The quality of evidence comparing probiotics and pla- 1049
990 remission in this situation, although in one study comparing cebo was rated as very low for several reasons (Table 19 in 1050
991 prednisolone to fluticasone, symptoms improved more accompanying technical review). There was inconsistency 1051
992 rapidly with prednisolone.145 Second-generation cortico- in the type of probiotic formulations used and in the sum- 1052
993 steroids appear to have fewer corticosteroid-related side mary effect estimates. The RCTs were at high risk of bias, 1053
994 effects, but are significantly more costly than oral predni- with unclear allocation concealment and methods of 1054
995 sone. Therefore, the choice between budesonide MMX and randomization. Estimates of effect were imprecise with wide 1055
996 oral prednisone primarily involves trading-off costs and CIs crossing 1. The evidence comparing probiotics and 1056
997 potential for adverse events. Patients who place higher mesalamine was rated as very low quality for very serious 1057
998 value on avoidance of side effects and lower value on imprecision and high risk of bias. 1058
999 avoiding costs can reasonably choose budesonide MMX in 1059
this situation. Lastly, patients who require repeated or pro- Recommendation 12. In patients with mild–moderate
1000 ulcerative colitis despite 5-ASA therapy, the AGA
1060
1001 longed corticosteroid courses should be considered for esca- 1061
lation to biologic therapies and/or immunomodulators.146 makes no recommendation for use of curcumin. No
1002 recommendation, knowledge gap. 1062
1003 The overall quality of evidence for this recommendation 1063
1004 was rated as low due to imprecision of the effect estimates 1064
1005 (Tables 12 and 13 in accompanying technical review). It was Due to limited evidence, the AGA makes no recommen- 1065
1006 also rated down for indirectness, as other second- dation for adding curcumin in patients with mild–moderate 1066
1007 generation corticosteroids and not budesonide MMX were UC despite 5-ASA therapy. Pooled results from 3 RCTs 1067
1008 used in the available RCTs. enrolling 169 patients with mild–moderate symptoms 1068
AGA SECTION
1009 despite standard-dose mesalamine showed a trend to a 1069

Recommendation 11. In patients with mild–moderate benefit for oral curcumin over placebo159–161 (RR, 0.70;
1010 ulcerative colitis, the AGA makes no
1070
1011 95% CI, 0.48–1.03), with considerable heterogeneity. These 1071
recommendation for use of probiotics. No
1012 recommendation, knowledge gap. 3 studies used widely varying doses of curcumin (150 mg to 1072
1013 3 g/d). The only strongly positive study had an exception- 1073
1014 ally low placebo response (12.5%) and remission rates 1074
1015 The AGA makes no recommendation for use of probiotics (0%).161 A single small trial of maintenance therapy in 1075
1016 in patients with mild–moderate UC. Seven RCTs enrolling patients also taking mesalamine showed benefit of adding 1076
1017 585 patients were identified, and probiotics were not oral curcumin over placebo in maintaining remission162 1077
1018 more effective than placebo for inducing remission147–153 (RR, 0.30; 95% CI, 0.11–0.85). 1078
1019 1079
1020 1080

1081 Curcumin has immunomodulatory, pro-apoptotic, and (2.5%).169 Another potential adverse effect is the theoretic 1141
1082 anti-angiogenic properties that have sparked interest in its risk for transmission of infections or chronic diseases, such 1142
1083 use for immune-mediated diseases.163 Because of curcu- as obesity and autoimmune conditions.170 Large studies 1143
1084 min’s taste and color, it is difficult to develop true placebos with long-term follow-up are needed to help understand 1144
1085 for RCTs, and studies of its efficacy are at risk of bias due to these risks. 1145
1086 inadequate blinding. Curcumin is generally well tolerated The use of FMT for treatment of UC should be consid- 1146
1087 without significant harmful effects. The potential risk of ered experimental at this time, and the Food and Drug 1147
1088 using curcumin is delaying more effective therapy with Administration does not currently allow FMT for indications 1148
1089 potential for symptom progression. Larger well-designed other than C difficile infection unless conducted as part of a 1149
1090 studies of curcumin are needed to define its role in clinical trial. The use of FMT also risks delay in initiation of 1150
1091 patients who do or do not respond to proven therapy, such proven therapy, with possible ongoing or worsening disease 1151
1092 as oral or topical 5-ASA and to evaluate its effectiveness for activity. Further mechanistic and clinical studies are needed 1152
1093 maintenance. to determine whether FMT will be beneficial in this patient 1153
1094 The overall body of evidence for curcumin in induction population. 1154
1095 of remission was rated as very low quality due to high risk The overall evidence for FMT in induction of remission 1155
1096 of bias, inconsistency, and imprecision due to low event was rated as low due to inconsistency in the interventions 1156
1097 rates and wide CIs for the effect estimates (Table 20 in studied and imprecision from low event rates (Table 21 in 1157
1098 accompanying technical review). The evidence for mainte- accompanying technical review). The quality of evidence for 1158
1099 nance of remission was rated as very low quality due to FMT in maintenance of remission was rated as very low 1159
1100 serious imprecision because only 1 small trial was because only small, non-comparative cohort studies of 1160
1101 identified. heterogeneous patients were available. 1161
1102 1162
1103 1163
1104
UC without Clostridium difficile infection, the AGA Summary 1164
recommends fecal microbiota transplantation be These practice recommendations for the management of
1105 performed only in the context of a clinical trial. No 1165
1106 recommendation for treatment of ulcerative colitis, mild–moderate UC were developed using the GRADE 1166
1107 knowledge gap. framework and in adherence to the standards set forth by 1167
1108 the Institute of Medicine for creation of trustworthy 1168
1109 guidelines.9,10 They are intended to reduce practice varia- 1169
1110 The AGA recommends that FMT be performed only in tion and promote high-quality, high-value care for patients 1170
1111 the context of a clinical trial for patients with mild– with mild–moderate UC. 1171
1112 moderate UC who do not have Clostridium difficile infec- The current evidence supports use of standard-dose 1172
1113 tion. Pooled analysis of 4 RCTs enrolling 281 patients with mesalamine or diazo-bonded 5-ASAs for induction and 1173
1114 active symptoms showed that FMT was more effective in maintenance of remission in patients with extensive mild– 1174
1115 inducing clinical remission (RR, 0.80; 95% CI, 0.71–0.89) moderate UC. Use of combined oral and rectal 5-ASA in 1175
1116 and endoscopic remission164–167 (RR, 0.77; 95% CI, 0.63– patients with extensive disease may improve rates of 1176
1117 0.93). FMT and placebo were similarly well tolerated. No induction of remission, as may escalation to high-dose oral 1177
1118 RCTs of FMT for maintenance of remission were identified. with rectal 5-ASA in patients with suboptimal response to 1178
1119 However, a meta-analysis of 5 non-comparative cohort standard-dose therapy. Those with moderate symptoms 1179
1120 studies was identified, including 44 patients who received may benefit from early use of combined oral and rectal 1180
1121 1–5 FMTs.164 Of the 44 patients, 22 had clinical response, 16 5-ASA. Patients with proctosigmoiditis or proctitis can be 1181
1122 were unchanged, and 3 patients deteriorated over 4–72 treated with topical mesalamines rather than oral 5-ASA. 1182
1123 months of follow-up. Those patients with suboptimal response or intolerance to 1183
1124 The RCTs of FMT were quite heterogeneous in route of rectal mesalamine may opt to use rectal corticosteroids 1184
1125 administration and inclusion criteria. FMT was variously enemas or foams. Patients with inadequate response to 1185
1126 delivered by colonoscopy followed by 2 enemas,168 enemas optimized 5-ASA require escalation of therapy to oral 1186
1127 administered 5 days per week for 8 weeks,166 weekly en- prednisone or budesonide MMX. 1187
1128 emas for 6 weeks,165 or 2 nasoduodenal tube infusions We identified several knowledge gaps and areas for 1188
separated by 3 weeks.167 The source and quantity of
AGA SECTION
1129 future research in this patient population. Due to evidence 1189

1130 transplanted stool differed between studies, as did the gaps, the AGA makes no recommendation for use of pro- 1190
1131 comparator (autologous stool in 2 trials, water in 2 trials). biotics, curcumin, or FMT in patients with mild–moderate 1191
1132 Because of this heterogeneity, there is no evidence to guide UC. Although these modalities appear to be safe, their use 1192
1133 practitioners in terms of appropriate donors, dose, route, or risks delaying proven effective therapy with the potential 1193
1134 schedule of administration for FMT. for worsening symptoms or complications. Thus, further 1194
1135 FMT is generally well-tolerated, with few serious studies of their efficacy and safety compared to those of the 1195
1136 adverse events in the RCTs for UC. A meta-analysis of 50 therapies recommended here are urgently needed. Devel- 1196
1137 studies of FMT for UC or other indications (primarily opment and validation of risk-stratification tools to identify 1197
1138 recurrent C difficile infection) showed serious adverse patients who have mild–moderate symptoms but who are at 1198
1139 events in 9.2%, including death (3.5%) and infection high risk of progression to moderate–severe disease and/or 1199
1140 1200

colectomy are needed. Better understanding of optimal 13.Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily,
1201 1261
dosing regimens, in particular, which patients might benefit high-concentration MMX mesalamine in active ulcerative
1202 1262
from initial use of high-dose mesalamine or topical mesal- colitis. Gastroenterology 2007;132:66–75.
1203 1263
amine, is also required. We also identified a need to better 14.Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of
1204 1264
understand the relative effectiveness and side effects of once- or twice-daily MMX mesalamine (SPD476) for the
1205 1265
budesonide and systemic corticosteroids in patients who do induction of remission of mild to moderately active
1206 1266
not respond adequately to 5-ASAs. Finally, studies to iden- ulcerative colitis. Clin Gastroenterol Hepatol 2007;5:
1207 95–102. 1267
1208 tify the appropriate patient and timing for escalation to 1268
immunomodulators and/or biologics would help with 15.Sutherland LR, Robinson M, Onstad G, et al. A double-
1209 blind, placebo controlled, multicentre study of the effi- 1269
1210 targeting therapy appropriately. 1270
cacy and safety of 5-aminosalicylic acid tablets in the
1211 treatment of ulcerative colitis. Can J Gastroenterol 1990; 1271
1212 4:463–467. 1272
1213 References 16.Hanauer S, Schwartz J, Robinson M, et al. Mesalamine 1273
1214 1. Singh S, Feuerstein JD, Binion DG, et al. American capsules for treatment of active ulcerative colitis: results 1274
1215 Gastroenterological Association technical review on the of a controlled trial. Pentasa Study Group. Am J Gas- 1275
1216 management of mild-moderate ulcerative colitis. troenterol 1993;88:1188–1197. 1276
1217 Gastroenterology 2018. 17.Pontes C, Vives R, Torres F, et al. Safety and activity of 1277
1218 2. Fumery M, Singh S, Dulai PS, et al. Natural history of dersalazine sodium in patients with mild-to-moderate 1278
1219 adult ulcerative colitis in population-based cohorts: a active colitis: double-blind randomized proof of 1279
1220 systematic review. Clin Gastroenterol Hepatol 2017; concept study. Inflamm Bowel Dis 2014;20:2004–2012. 1280
1221 16:343–356 e3. 18.Sninsky CA, Cort DH, Shanahan F, et al. Oral mesal- 1281
1222 3. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final amine (Asacol) for mildly to moderately active ulcerative 1282
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1729 Rectum 1992;35:923–927. 1789
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1854 2218–2227. duration, low intensity, pooled fecal microbiota 1914
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1859 1919
1860 1920

169.Wang S, Xu M, Wang W, et al. Systematic review: Seattle, WA; Thiruvengadam Muniraj, Yale University, Milford, CT; Robert
1921 O’Shea, Cleveland Clinic, University Heights, OH; John Pandolfino, 1981
adverse events of fecal microbiota transplantation. PLoS
1922 Northwestern University, Chicago, IL; Amit Patel, Duke University, Cary, NC; 1982
One 2016;11:e0161174. Ravi Sharaf, North Shore Long Island Jewish Health System, New Hyde
1923 Park, NY; Shazia Siddique, University of Pennsylvania, Philadelphia, PA; 1983
170.Cammarota G, Ianiro G, Tilg H, et al. European
1924 Grace Su, University of Michigan, Ann Arbor, MI; Kenneth Wang, Mayo 1984
consensus conference on faecal microbiota trans- Clinic, Rochester, MI; Adam Weizman, Mount Sinai Hospital, Toronto, ON.
1925 1985
plantation in clinical practice. Gut 2017;66:569–580.
1926 Conflicts of interest 1986
1927 All members were required to complete the disclosure statement. These Q4 1987
statements are maintained at the American Gastroenterological Association
1928 Reprint requests headquarters in Bethesda, Maryland, and pertinent disclosures are published 1988
1929Q1 Q2 Address requests for reprints to: ---. with this report. 1989
1930 Acknowledgments This document presents the official recommendations of the American 1990
1931Q7 Q3 The American Gastroenterological Association Clinical Guidelines Committee Gastroenterological Association (AGA) on the management of mild-to- 1991
included Seth Crockett, University of North Carolina at Chapel Hill, NC; moderate ulcerative colitis. The guideline was developed by the AGA’s
1932 Yngve Falck-Ytter, Veterans Affairs and Case Medical Center Cleveland; Clinical Practice Guideline Committee and approved by the AGA Governing 1992
1933 Joseph Feuerstein, Beth Israel Deaconess Medical Center, Brookline, MA; Board. Development of this guideline and its accompanying technical 1993
1934 Steven Flamm, Northwestern University, Chicago, IL; John Inadomi,
University of Washington, Seattle, WA; Cynthia Ko, University of Washington,
review was fully funded by the AGA Institute with no additional outside
funding.
1994
1935 1995
1936 1996
1937 1997
1938 1998
1939 1999
1940 2000
1941 2001
1942 2002
1943 2003
1944 2004
1945 2005
1946 2006
1947 2007
1948 2008
1949 2009
1950 2010
1951 2011
1952 2012
1953 2013
1954 2014
1955 2015
1956 2016
1957 2017
1958 2018
1959 2019
1960 2020
1961 2021
1962 2022
1963 2023
1964 2024
1965 2025
1966 2026
1967 2027
1968 2028
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1969 2029
1970 2030
1971 2031
1972 2032
1973 2033
1974 2034
1975 2035
1976 2036
1977 2037
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1979 2039
1980 2040

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Gastroenterology 2019;-:1–17

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121 Table 1.Characteristics of Available 5-Aminosalicylates and Sulfasalazine 181

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289 preferences. 349

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409 (RR, 0.63; 95% CI, 0.55–0.78). No beneﬁt of high-dose 469

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769 technical review). 829

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1009 despite standard-dose mesalamine showed a trend to a 1069

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1129 future research in this patient population. Due to evidence 1189

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1249 Trust. Washington, DC: National Academies Press, 2011. 1309

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the treatment of acute mild-to-moderate ulcerative coli-

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1609 inferiority trial. Gut 2009;58:233–240. Colitis 2010;4:153–160. 1669

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enema study group. Gastroenterology 1998;115:

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PGL 5.5.0 DTD YGAST62322_proof 27 December 2018 5:20 pm ce

PGL 5.5.0 DTD YGAST62322_proof 27 December 2018 5:20 pm ce

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