American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis

Gastroenterology 2015;-:1–28 American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis Q30...

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Gastroenterology 2015;-:1–28

American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis Q30

Darrell S. Pardi,1 William J. Tremaine,1 and Alonso Carrasco-Labra2,3 1 Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; 2McMaster University, Hamilton, Ontario, Canada; and 3Evidence-Based Dentistry Unit, Faculty of Dentistry, Universidad de Chile, Santiago, Chile

Q3

Q4

M

icroscopic colitis (MC) is a cause of chronic diarrhea, and there are 2 subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). The clinical features, symptoms, and responses to treatment are similar for both CC and LC. All meta-analyses conducted for this technical review tested for interaction (or a subgroup effect), and in every case there was no evidence of a subgroup effect. Therefore, in this review, the 2 subtypes are combined and considered together as MC. Information on pathophysiology was considered outside the scope of this review. The prevalence of MC has been reported in recent studies to be 48 per 100,000 in Spain, 123 per 100,000 in Sweden, and 219 per 100,000 in Minnesota. MC is more common in people 60 years of age and older, and there is an apparent female preponderance. The clinical course of MC is variable; symptoms range from mild (a few loose stools daily) to severe (incapacitating watery diarrhea and abdominal pain). Symptoms can persist for months to years or spontaneously remit and then recur after months to years. Diagnosis of MC is based on compatible histology from colonic mucosal biopsy specimens obtained during colonoscopy or ﬂexible sigmoidoscopy. The distribution of colonic involvement can be patchy or segmental, so multiple random biopsy specimens are often required for diagnosis. Quality of life is impaired in patients with MC in proportion to the degree of diarrhea, abdominal pain, urgency, and incontinence and to a similar degree to that reported for active irritable bowel disease. A diagnosis of MC does not increase mortality or the risk of colorectal cancer and only rarely requires surgery. The goal of treatment of MC is to induce remission while minimizing potential adverse effects of therapy. Some patients remain asymptomatic after induction of remission and after discontinuing therapy and do not need maintenance treatment for MC. However, many patients have a symptomatic recurrence after discontinuation of treatment and should be considered for maintenance therapy. Medications that are used to treat MC include loperamide (an antidiarrheal agent); bismuth subsalicylate (an antimicrobial, anti-inﬂammatory agent); colesevelam, cholestyramine, and colestipol (bile acid binders); mesalamine (an anti-inﬂammatory agent); prednisone and budesonide (corticosteroids); azathioprine and methotrexate (immune suppressants); inﬂiximab and adalimumab (biologic agents); and surgical interventions (diverting ileostomy and

proctocolectomy with ileal pouch–anal anastomosis). Several of these therapies are used in clinical practice but have not been studied in clinical trials. These therapies are therefore not addressed directly in this technical review.

Methods Focused Questions The methods used to identify, select, and summarize the evidence are described at a question level. This technical review is not intended to be a review of all aspects of MC. Rather, it summarizes the evidence related to the following questions. Question 1. What is the prevalence of MC? How many colon biopsy specimens should be obtained and from which areas of the colon? This question is for information and not a recommendation, and therefore it was not framed as a PICO (population, interventions, comparisons, and outcomes) question. The content of this question is included in the guideline only for information.

Q5

Question 2. In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? The population is adult patients with MC (either LC or CC). The interventions include bismuth subsalicylate, budesonide, cholestyramine, sulfasalazine, mesalamine, prednisone, azathioprine, metronidazole, methotrexate, inﬂiximab, adalimumab, or any other medication described. The comparisons include any of the medications described as an intervention, compared in a head-to-head fashion or compared with placebo or no treatment. The outcomes include clinical response, histological response, quality of life, and adverse events according to the outcome description in the included studies.

Abbreviations used in this paper: CC, collagenous colitis; CI, conﬁdence interval; GIQLI, Gastrointestinal Quality of Life Index; GRADE, Grading of Recommendations Assessment, Development and Evaluation; LC, lymphocytic colitis; MC, microscopic colitis; MD, mean difference; PICO, population, interventions, comparisons, and outcomes; RR, relative risk; SIBDQ, Short Inﬂammatory Bowel Disease Questionnaire. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.11.006

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120

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Question 3. In patients successfully treated for MC (either LC or CC) and in remission of symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events? The population is adult patients successfully treated for MC (either LC or CC) and in remission of symptoms. The interventions include budesonide, a thiopurine agent (azathioprine), or any other intervention described in the literature for maintaining remission of MC. The comparisons include head-tohead comparisons among any of the interventions identiﬁed, placebo, or no treatment. The outcomes include maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events, as described in the included studies. A summary of the focused questions and PICO components is shown in Table 1.

Deﬁnition of the Relative Importance of Outcomes After deﬁning the included outcomes for each focused question, an online survey was circulated among panel members participating in this review. In this survey, participants were asked to rank the outcomes according to their relative importance. The process was conducted individually and independently. In the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the relative importance of an outcome is deﬁned on a scale from 1 (least important) to 9 (most critical); those rated from 1 to 3 are deﬁned as of limited importance, from 4 to 6 as important, and from 7 to 9 as critical.1 The panel was not aware of the quality of the evidence for each of the outcomes at the moment of assessing their importance. The results of the determination of the relative importance of the outcomes are shown in Table 2.

Study Selection Criteria and Search Strategy per Question Question 1. What is the prevalence of MC? How many colon biopsy specimens should be obtained and from which areas of the colon?

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121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180

Pardi et al

Study selection criteria. We included studies recruiting patients with both LC and CC. For estimation of the prevalence of the disease, we selected studies based on populations of patients with chronic diarrhea. These studies also provided a description of the diagnostic test used, number of biopsy specimens obtained, and areas of the colon from which biopsy specimens were obtained. We excluded editorial letters, comments, notes, or case reports. Search strategy and databases. We searched Ovid MEDLINE, Ovid EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of

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Systematic Reviews from inception to August 2014. The search strategy included terms such as “microscopic colitis,” “colonoscopy,” and “biopsy,” among others. There was no restriction by language or status of publication. For more details about the search strategy, see Appendix 1. Question 2. In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events?

Study selection criteria. We included studies that recruited participants with a conﬁrmed diagnosis of MC, irrespective of whether the patients had CC or LC. In addition, the studies provided information about the effectiveness and safety proﬁle of any medication to treat these conditions compared with other interventions in a head-to-head comparison or placebo. For this question, we excluded studies reporting on the effect of interventions for maintaining remission of MC, because these studies are covered in question 3. Given that we were anticipating scarce evidence to answer this question, we included both randomized controlled trials and observational studies during the initial screening process. Good-quality observational studies were included in the review along with the controlled trials. Search strategy and databases. We searched Ovid MEDLINE from 1946 to July week 4 2014, Ovid EMBASE from 1980 to 2014 week 31, the Cochrane Central Register of Controlled Trials (CENTRAL) to June 2014, and the Cochrane Database of Systematic Reviews from 2005 to June 2014. The search strategy included terms describing the disease and all medications available for inducing remission of MC. There was no restriction by language. We excluded editorial letters, comments, notes, or case reports. For more details about the search strategy, see Appendix 2. Question 3. In patients successfully treated for MC (either LC or CC) and in remission of symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events?

Study selection criteria. We included treatment trials for patients with a conﬁrmed diagnosis of MC, including both CC and LC, who were in clinical remission. Studies were selected that included information about the effectiveness and safety proﬁle of any medication to maintain remission. We included interventions for maintaining remission compared with other interventions or placebo. We excluded studies reporting on the effect of interventions for inducing remission of MC because those studies were addressed in question 2. Because we anticipated scarce evidence to answer this question, we initially included both randomized controlled trials and observational studies. Good-quality observational studies were included in the review along with the controlled trials. Search strategy and databases. We searched Ovid MEDLINE from 1946 to July week 4 2014, Ovid EMBASE from 1980 to 2014 week 31, the Cochrane Central Register of Controlled Trials (CENTRAL) to June 2014, and the Cochrane Database of Systematic Reviews from 2005 to June 2014. The

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181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 -

2015

Table 1.Focus Review Questions and PICO Description

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Question

Population

1 What is the prevalence of MC? How Patients with both LC and CC; for estimation of the prevalence of the many colon biopsy specimens should be obtained and from which areas of disease, we selected studies based on populations of patients with either the colon? nonspeciﬁc chronic watery diarrhea or chronic diarrhea refractory to treatment Adult patients with MC (either LC or CC) 2 In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events?

Intervention or new test Colonoscopy with mucosal biopsy specimens in patients with chronic diarrhea

Bismuth subsalicylate Budesonide Cholestyramine Sulfasalazine Mesalamine Prednisone Azathioprine Metronidazole Methotrexate Inﬂiximab Adalimumab Other medication reported in the literature Adult patients successfully treated for Budesonide Thiopurine agent 3 In patients successfully treated for MC MC (either LC or CC) and in remission (azathioprine) (either LC or CC) and in remission of of symptoms symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events?

Comparison or gold standard

Outcome

Not applicable

Number of biopsy specimens required and areas of the colon selected

Head-to-head comparison, placebo/no treatment

Clinical response (decreased fecal frequency and/or stool weight), histological response, quality of life, adverse events

Placebo/no treatment (observation)

Maintenance of clinical response (number of patients with a maintained clinical response or lack of clinical relapse), maintenance of histological response, time to relapse, effect on quality of life, adverse events

AGA Section 3

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301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360

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Table 2.Relative Importance of Outcome per Comparison Question In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? In patients successfully treated for MC (either LC or CC) and in remission of symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events?

Q6

Outcomes Clinical response Histological response Adverse events Quality of life Maintenance of clinical response Maintenance of histological response Time to relapse during maintenance therapy Time to relapse after maintenance therapy Adverse events Quality of life

search strategy included terms describing the disease and all medications available for maintaining remission of MC. There was no restriction by language. We excluded editorial letters, comments, notes, or case reports. For more details about the search strategy, see Appendix 2.

Study Selection Process After removing duplicates, 2 researchers independently assessed the retrieved references for eligibility using the title and abstract. References that showed potential eligibility were assessed again in duplicate and independently, this time using full text. A piloted form including the main eligibility criteria helped to document this process. When there was disagreement, a third person arbitrated to make the ﬁnal inclusion decision.

Data Extraction and Analysis

AGA SECTION

361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420

Pardi et al

Using a piloted form, data extraction was conducted by one researcher and a second reviewer checked for accuracy. The information retrieved from primary studies included their main features, type of design, patient characteristics, clinical and histological deﬁnition of MC, risk of bias assessment, and outcomes measured. When feasible, contingency tables were created for each dichotomous outcome, and the relative risk (RR) and its 95% conﬁdence interval (CI) was calculated. When data from intention-to-treat analysis were shown, this was preferred over per-protocol analysis. The only exception to this was the outcome of adverse events, for which per-protocol analysis was performed. For continuous outcomes, the mean difference (MD) and its 95% CI was calculated. To facilitate decision making, the data from studies reporting clinical relapse during the maintenance period were transformed from the number of patients free from relapse to the number of participants having the event. When aggregated data such as standard deviation for a group were missing, the exact P value was used to approximate it. A random effects model was chosen a priori given that different dosages and methods of administration of medications were expected, representing a distribution of results of effectiveness. Review Manager 5.3 software (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) was use to conduct the meta-analyses.

Rating score

Relative importance

9 6 7 7 9 6 8

Critical Important Critical Critical Critical Important Critical

8

Critical

7 7

Critical Critical

Risk of Bias Assessment of Included Studies To determine the risk of bias of included studies, the Cochrane Risk of Bias Tool for randomized controlled trials2 and diagnostic test accuracy studies3 were used. For randomized controlled trials, the following domains were considered: (1) Was the random sequence adequately generated? (2) Was the allocation adequately concealed? (3) Were participants blinded to the intervention received? (4) Were personnel blinded to the intervention administered? (5) Were outcome adjudicators blinded to the intervention administered? (6) Was the study affected by incomplete outcome data? (7) Was the study affected by selective outcome reporting? (8) Was any other additional bias identiﬁed? The domains considered to assess the risk of bias of diagnostic test accuracy were as follows: (1) Was the spectrum of patients representative of the patients who will receive the test in practice? (2) Is the reference standard likely to classify the target condition correctly? (3) Is the time period between the reference standard and the index test short enough to be reasonably sure that the target condition did not change between the 2 tests? (4) Did the whole sample, or a random selection of the sample, receive veriﬁcation using the intended reference standard? (5) Did patients receive the same reference standard irrespective of the index test result? (6) Was the reference standard independent of the index test (ie, the index test did not form part of the reference standard)? (7) Were the results of the reference standard interpreted without knowledge of the results of the index test? (8) Were the results of the index test interpreted without knowledge of the results of the reference standard? (9) Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? (10) Were withdrawals from the study explained? This assessment was conducted in duplicate by 2 independent evaluators.

Evaluation of the Quality of the Body of Evidence The quality of the body of evidence (also known as conﬁdence or certainty in the evidence) across outcomes was assessed using the GRADE approach.1 In this approach, randomized controlled trials start as high-quality evidence; however, the conﬁdence in the estimates of effect can be downgraded from high to moderate, low, or very low when

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421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480

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serious or very serious issues related to risk of bias, imprecision, indirectness, inconsistency, and publication bias are identiﬁed. For diagnostic test accuracy studies using a crosssectional design, the quality of the evidence starts as high and the same domains were assessed to determine whether downgrading was necessary.4 Results were tabulated using evidence proﬁles and evidence to decision tables. The Guideline Development Tool (GDT) software was used to assess and record judgments related to the quality of evidence assessment and move from the evidence to decisions (www. guidelinedevelopment.org).

5

References idenƟfied in the databases (n=1239)

Duplicated references (n=402)

References for Ɵtle and abstract screening (n=837)

Results Systematic Search Retrieval and Study Selection Question 1. What is the prevalence of MC? How many colon biopsy specimens should be obtained and from which areas of the colon? The search strategy retrieved 1239 articles, of which 402 were duplicates. The remaining 837 references went to the title and abstract screening stage. Then, 51 were included for full-text screening. A total of 29 primary studies proved eligible (Figure 1).

Excluded references (n=786)

References for full text screening (n=51)

Question 2. In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? The search strategy retrieved 592 articles, of which 162 were duplicates. The remaining 430 references went to the title and abstract screening stage. Then, 76 were included for full-text screening. A total of 12 primary studies proved eligible (Figure 2). Question 3. In patients successfully treated for MC (either LC or CC) and in remission of symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events? The search strategy retrieved 592 articles, of which 162 were duplicates. The remaining 430 references went to the title and abstract screening stage. Then, 80 were included for full-text screening. A total of 3 primary studies proved eligible (Figure 3).

Excluded references (n=22)

Included studies (n=29)

print & web 4C=FPO

Q7

AGA Section

Figure 1. Flow chart retrieval and study selection for the prevalence and biopsy characteristics of patients with MC.

as a background question. Its content is included in the guideline (these studies are not included in the current review). Studies included in questions 2 and 3. Table 3 shows a detailed description of the included studies. These studies were published between 1999 and 2014 and conducted in Belgium, Germany, Denmark, Lithuania, and Italy. The proportion of female participants ranged from 67% to 93%. The mode for the age was 60 years. Follow-up ranged from 2 to 25 weeks. For more details about these studies and their characteristics, interventions, and comparisons, see Table 3.

Description of Included Studies Studies included in question 1. The purpose of this question was to inform clinicians about the prevalence of the disease and the number of biopsy specimens that should be taken along with the areas from the colon that need to be considered. This question was not framed as a PICO question linked to a recommendation because this was classiﬁed

Risk of Bias Assessment of Included Studies Randomized controlled trials. Of the 15 included randomized controlled trials, 7 were assessed as unclear for the domain related to the way the random sequence generation was created.5–12 In the allocation concealment Q8 domain, 10 of 15 trials were assessed as unclear risk of bias

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AGA SECTION

481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540

2015

541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600

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References idenƟfied in the databases (n=592)

Duplicated references (n=162)

References for Ɵtle and abstract screening (n=430)

Excluded references (n=354)

References for full text screening (n=76)

print & web 4C=FPO

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No.

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This question is not about the effect of any intervention. The results of these studies are included in the guideline. Question 2. In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events?

Bismuth subsalicylate versus no treatment for inducing remission. Only one randomized controlled trial reported results comparing bismuth subsalicylate (eight 262-mg chewable tablets [Pepto-Bismol; Procter & Gamble, Cincinnati, OH] per day for 8 weeks in 3 doses: 3 tablets in the morning, 2 at midday, and 3 in the evening) with placebo (Table 4).19 This small trial included 14 participants and has Q10 only been published as an abstract. Because there were no events in the control arm for the clinical response and adverse events outcomes, it was not possible to calculate absolute and relative estimates.20 There was a 206%

References idenƟfied in the databases (n=592)

Excluded references (n=64)

Duplicated references (n=162)

Included studies (n=12) References for Ɵtle and abstract screening (n=430)

Figure 2. Flow chart retrieval and study selection for inducing remission of MC.

due to limited information regarding the methods used to protect the sequence at the moment of randomization. The domain that had the highest risk of bias classiﬁcation was the one asking whether selective outcome reporting was present.5,7–13 Frequently, the investigators did not provide numerical data for outcomes when the study failed to show statistical signiﬁcance and did not report measures of variability for continuous outcomes; some of the investigators did not report relevant outcomes such as histological response and quality of life. Three trials showed Q9 low risk of bias overall14–16 (Figure 4).

Excluded references (n=350)

References for full text screening (n=80)

Excluded references (n=77)

Effect of the Interventions and Assessment of the Quality of the Evidence Included studies (n=3)

Question 1. What is the prevalence of MC? How many colon biopsy specimens should be obtained and from which areas of the colon?

Figure 3. Flow chart retrieval and study selection for maintaining remission of MC.

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print & web 4C=FPO

AGA SECTION

601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660

Pardi et al

661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720

721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 -

Table 3.Characteristics of Included Randomized Controlled Trials

n

Type of Female colitis (%)

Baert et al, 20025

28

CC

71

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Bonderup et al, 20036

20

CC

80

Bonderup et al, 200923

34

CC

79

Calabrese et al, 200722

LC: 41 CC: 23

LC, CC

LC: 71 CC: 74

Mean age (y) 56

54

Age range or SD (y) 15

40–80

Treatment and comparator

Duration of follow-up

Budesonide one 9-mg dose daily vs placebo

8 wk

Budesonide 9 mg/4 wk, 6 mg/2 wk, 3 mg/2 wk vs placebo

8 wk

Treatment: 62.8 Comparator: 58.4

Treatment: 42–81 Comparator: 33–82

Budesonide 6 mg/day vs placebo

25 wk

LC: 40.4 CC: 41.6

LC: 13.7 (19–65) CC: 12.5 (28–68)

Mesalazine 800 mg vs mesalazine 800 mg þ cholestyramine 4 g

25 wk

2015

Author (year)

Inclusion criteria Clinical: 2 mo of chronic watery diarrhea (at least 3 semi-loose or loose stools per day) and no other cause for diarrhea on history and full clinical examination Histological: subepithelial collagen band with feathery appearance of the inferior border exceeding 10 Dm; increased mixed inﬂammatory cell inﬁltrate in mononuclear lamina propria Clinical: Older than 18 y with clinically active CC (stool frequency >4 daily or stool wt >200 g/day) Histological: collagen layer >10 mm beneath the surface epithelium in colonic mucosa

Exclusion criteria Stool examination with pathogens, parasites, and Clostridium difﬁcile toxin; signiﬁcant gastrointestinal disease

Q23

AGA Section

Treatment with anti-inﬂammatory drugs within the past 3 mo; chronic gastrointestinal diseases; stool samples positive for pathogens, parasites, and ova; clinically signiﬁcant renal or hepatic disease; pregnant or breast-feeding women Older than 18 y with histologically Treatment with salazopyrin, conﬁrmed CC (diffuse 5-aminosalicylic acid, lymphocytic inﬂammation and budesonide, or a systemic evidence of a collagenous glucocorticoid during the past band >10 mm, at least focally 3 mo or ketoconazole during upon) the past 7 days Clear correlation between Clinical: Chronic or recurrent symptoms and treatment with watery nonbloody diarrhea medication (ie, NSAIDs, Histological: increased chronic ticlopidine, and proton pump inﬂammatory inﬁltrate in the inhibitors) lamina propria, increased number of IELs and damage of surface epithelium, with ﬂattening of epithelial cells and/or epithelial loss and detachment and minimal crypt architecture distortion

Q22

7

AGA SECTION

781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840

841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 AGA SECTION

Fine et al, 199919

n

Type of Female colitis (%)

Mean age (y)

Age range or SD (y)

Treatment and comparator

Duration of follow-up

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9

CC

NR

NR

NR

Bismuth subsalicylate (nine 262-mg chewable tablets daily in 3 divided doses) vs placebo

25 wk

Latella et al, 20107

46

LC

NR

NR

NR

8 wk

Madisch et al, 200713

31

CC

BS: 87 Pl: 80

Median BS: 64.5 Pl: 53

NR

Beclomethasone dipropionate 5 mg/ day vs beclomethasone dipropionate 10 mg/ day vs mesalazine 2.4 mg/day Boswellia serrata 400 mg per capsule 3 times daily vs placebo

Miehlke et al, 200214

51

CC

76

BS: 60 Pl: 60

BS: 32–78 Pl: 36–75

Budesonide one 9-mg dose daily vs placebo

6 wk

6 wk

Inclusion criteria

Pardi et al

Author (year)

8

Table 3. Continued Exclusion criteria

Clinical: 8 wk of nonbloody watery No evidence of Crohn disease diarrhea (without steatorrhea) Histological: excess of mononuclear inﬂammatory cells in the lamina propria and surface epithelium without signiﬁcant neutrophilia or eosinophilic inﬂammation, numerous crypt abscesses, or granuloma Clinical: NR NR Histological: LC

Clinical: 5 liquid or soft stools daily on average per week Histological: histologically conﬁrmed diagnosis of CC

Q24

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Treatment with budesonide, salicylates, steroids, prokinetics, antibiotics, ketoconazole, or NSAIDs within 4 weeks before randomization, other endoscopically or histologically veriﬁed causes for diarrhea, infectious diarrhea, pregnancy or lactation, previous colonic surgery, known intolerance to BSE Clinical: 18–80 y of age and use of Evidence of infectious diarrhea; effective contraception, at treatment with budesonide, least 5 liquid or soft stools salicylates, corticosteroids, daily on average per week prokinetics, antibiotics, Histological: histologically ketoconazole, or NSAIDs conﬁrmed diagnosis of CC within the past 4 wk before randomization; endoscopic-histological ﬁndings that may have caused diarrhea; known intolerance to budesonide, pregnancy, or lactation; history of partial colonic resection

No. -

901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960

961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 -

Table 3. Continued n

Type of Female colitis (%)

Mean age (y)

Miehlke et al, 20088

46

CC

73

57.5

Miehlke et al, 200915

42

LC

67

Median: 61

Age range or SD (y)

Treatment and comparator

Duration of follow-up

34–78

Budesonide 6 mg once daily for 6 mo vs placebo

25 wk

BS: 36–80 Pl: 23–76

Budesonide one 9-mg dose daily vs placebo

6 wk

2015

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Author (year)

Inclusion criteria

Exclusion criteria

Older than 18 y with symptomatic Diarrhea with an infectious cause; and histologically proven CC; other chronic inﬂammatory 3 watery/loose stools daily on disease of the bowel; celiac 4 of the previous 7 days and a disease; malignancy; major history of diarrhea for 4 wk organ disease; previous surgery of the large bowel; current treatment with 5aminosalicylates, salicylates, systemic corticosteroids, antibiotics, or NSAIDs; use of budesonide within 14 days of enrollment; hypersensitivity to budesonide; pregnancy or lactation; alcohol/drug abuse Clinical: 18–80 y of age, 3 watery Other types of bowel disease, CC, Crohn disease, ulcerative or loose stools daily within 7 colitis or ischemic colitis, days before random celiac disease, malignancy or assignment any severe concomitant Histological: histologically disease, partial colonic conﬁrmed LC (20 resection, intolerance to IELs/100 epithelial cells) budesonide, pregnancy and lactation; patients treated with budesonide, aminosalicylates, corticosteroids, or antibiotics during the 4 wk before random assignment

AGA Section 9

AGA SECTION

1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080

1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 AGA SECTION

10

Table 3. Continued n

Type of Female colitis (%)

Miehlke et al, 201416

92

CC

82.6

58.8

Munch et al, 20149

84

CC

85

58.8

Munck et al, 200310

12

CC

83

Mean age (y)

Pr: 60 Pl: 63

Age range or SD (y)

Treatment and comparator

Duration of follow-up

12.9

Budesonide one 9-mg dose daily vs mesalamine one 3-g dose daily vs placebo

8 wk

11

Low-dose budesonide (Budenofalk 3-mg capsules) vs Prednisolone 50 mg once daily for 2 weeks and then 37.5 mg for one week vs placebo

Placebo

Pr: 42–75 Pl: 61–73

2 wk

Inclusion criteria

Pardi et al

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Author (year)

Exclusion criteria

Clinical: >4 watery/soft stools on Other signiﬁcant colonic diseases, partial colonic resection, at least 4 days during the week infectious diarrhea, celiac before baseline; >3 stools per disease, diarrhea caused by day on average within the 7 other organic diseases of the days before baseline, chronic gastrointestinal tract, diarrhea for at least 3 mo treatment with budesonide, before baseline Boswellia serrata extract, Histological: histologically salicylates, corticosteroids, conﬁrmed CC (thickness of antibiotics, cholestyramine, collagen band >10 mm, degeneration of surface NSAIDs, or other immunosuppressant drugs epithelium) within the wk before baseline, malignant disease, severe comorbidity, abnormal hepatic function or cirrhosis, renal insufﬁciency, active peptic ulcer disease, known intolerance or resistance to study drugs, pregnancy, breast-feeding Patients with CC still in remission NR after 12 mo

Gastroenterology Vol.

Clinical: Older than 18 y reporting Bile acid malabsorption and/or no response to cholestyramine, at least 3 mo with diarrhea steatorrhea, celiac disease, without blood or pus and with other gastrointestinal diseases stool volume of 350 g/day or or previous gastrointestinal 200 g/day and stool frequency surgery with the exception of of 5 times daily cholecystectomy, other Histological: mixed but serious diseases, abnormal predominantly chronic laboratory test results, inﬂammatory inﬁltrate in the treatment with lamina propria and either a immunosuppressive drugs lymphocytic inﬁltration of at within 3 mo or use of least 20% of epithelial crypt medications with a known cells (LC) and/or a effect on gastrointestinal subepithelial collagen bond function including antiulcer exceeding 10 m in a wellmedication, antacids, oriented biopsy (CC) antibiotics, and NSAIDs

Q25

-,

No. -

1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200

1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 -

Table 3. Continued n

Type of Female colitis (%)

Pardi et al, 200911

15

LC

80

Wildt et al, 200612

29

CC

93

Mean age (y) 59.7

Pro: 61 Pl: 57

Age range or SD (y)

Treatment and comparator

Duration of follow-up

NR

Budesonide one 9-mg dose daily vs placebo

8 wk

Pr: 36–73 Pl: 26–79

AB-Cap-10, a mixture of L acidophilus strain LA-5 and B animalis subsp lactis strain BB-12 vs placebo

12 wk

2015

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Author (year)

Inclusion criteria Clinical: adults Histological: histologically conﬁrmed LC (20 IELs/100 epithelial cells) Clinical: older than 18 y and presence of active untreated disease for at least 4 wk (>21 liquid or soft stools per week or stool weight >200 g/day) Histological: histological diagnosis of CC

Exclusion criteria NR

Pregnancy or breast-feeding, chronic liver or kidney disease, severe chronic disease of vascular or cardiopulmonary origin, malignancies, immunosuppressive disease or treatment, known inﬂammatory bowel disease besides CC, evidence of infectious diarrhea, former surgical procedures involving the gastrointestinal tract except for appendectomy, malabsorption syndromes, celiac disease

IELs, intraepithelial lymphocytes; NSAIDs, nonsteroidal anti-inﬂammatory drugs; NR, not reported; BS, xxxxxxx; Pl, xxxxxxx; Pr, xxxxxxx; Pro, xxxxxxxx.

Q26

AGA Section 11

AGA SECTION

1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320

AGA SECTION

1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380

Pardi et al

Gastroenterology Vol.

print & web 4C=FPO

12

-,

No.

-

Figure 4. Risk of Bias Assessment of the Included Randomized Controlled Trials.

increase in the histological response of participants receiving the intervention after 8 weeks of follow-up; however, this difference was not statistically signiﬁcant (RR, 3.06; 95% CI, 0.3–30.97). No participants experienced adverse events. Quality of life was not measured in the

context of this study. The quality of the evidence for all reported outcomes was low due to very serious imprecision.

Prednisolone versus no treatment for inducing remission of MC. Only one trial reported data comparing the effect of prednisolone (50 mg once daily for 2 weeks and then

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1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440

1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 -

2015

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Table 4.Bismuth Subsalicylate Versus No Bismuth Subsalicylate for Inducing Remission of MC19 Quality assessment No. of studies

Study design

Risk of bias

No. of patients

Other Bismuth Inconsistency Indirectness Imprecision considerations subsalicylate No treatment

Clinical response (follow-up: 8 wk) 1 Randomized Not serious Not serious trials Histological response (follow-up: 8 wk) 1 Randomized Not serious Not serious trials

Adverse events (follow-up: 8 wk) 1 Randomized Not serious Not serious trials Quality of life (not reported) — — — —

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance 44⃝⃝ Low

Not serious

Very seriousa

None

7/7 (100.0%)

0/7 (0.0%)b

Not estimable

Not serious

Very seriousa

None

6/7 (85.7%)

1/7 (14.3%)

RR, 3.06 294 more per 44⃝⃝ (0.3–30.97) 1000 (from Low 100 fewer to 4281 more)

Not serious

Very seriousc

None

0/7 (0.0%)

0/7 (0.0%)

Not estimable

Not estimable

—

—

See comment Not estimable

See comment

—

—

Not estimable

44⃝⃝ Low —

Critical

Important

Critical

Critical

NOTE. Author(s): Alonso Carrasco-Labra, William Tremaine, and Darrell Pardi. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Bismuth subsalicylate (eight 262-mg chewable tablets daily in 3 divided doses). Comparison: No bismuth subsalicylate (placebo). a Only 7 events in total. Because all participants in the intervention group and no participants in the control group experienced the outcome, the RR and absolute risk reduction could not be estimated. b Zero events in the placebo arm prevented estimation of absolute effect. c Zero adverse events in both arms prevented estimation of absolute and relative effects.

Q27

AGA Section 13

AGA SECTION

1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560

14

AGA SECTION

1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581Q11 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620

Pardi et al

Gastroenterology Vol.

37.5 mg for 1 week) with placebo (Table 5).10 This small trial included 12 participants. Because there were no events in the control arm for the outcome of clinical response, it was not possible to calculate absolute and relative estimates.20 The quality of evidence for this outcome was assessed as very low due to serious issues of risk of bias and very serious issues of imprecision. Adverse events associated with the intervention included the typical adverse effects related to the use of a corticosteroid and were not severe enough to cause participants to withdraw from the study. The quality of the evidence for this outcome was low due to serious issues of risk of bias and imprecision. Histological response and quality of life were not reported in this trial.

Budesonide versus no treatment for inducing remission of MC. The effect of budesonide (9 mg once daily [three 3mg capsules]) was based on 6 studies and one additional report published separately (Table 6).5,6,11,14–16,21 In total, 218 participants informed the outcome of clinical remission. In relative terms, budesonide increased the probability of experiencing clinical remission by 152% after 6 to 8 months of follow-up (RR, 2.52; 95% CI, 1.56 1.45–4.4), which in absolute terms implies that 572 more patients per 1000 would experience remission when receiving budesonide. The quality of the evidence for clinical remission was assessed as moderate due to serious inconsistency. Histological response was informed by 5 randomized controlled trials including 161 patients.5,6,14–16 Patients receiving budesonide were 150% more likely to have histological remission after 6 to 8 weeks of follow-up (RR, 2.5; 95% CI, 1.56–3.99). In absolute terms, 421 more patients per 1000 would experience this outcome. The quality of the evidence for this outcome was determined to be moderate due to serious issues of inconsistency. Two studies informed about the time to induce clinical remission.14,16 Given that the authors of one of the studies did not provide measures of variability, a meta-analysis was not possible. Seven to 13 days was the range of estimated mean days to induce clinical remission (range, 2–30 days). This outcome had moderate-quality evidence due to risk of bias. Five studies5,11,14–16 reported data on adverse events after 6 to 8 weeks of follow-up, but only 3 of them contributed to the meta-analysis.14–16 In relative terms, participants receiving budesonide have a 16% increase in the risk of experiencing mild or minor adverse events; however, the difference between groups was not statistically signiﬁcant (RR, 1.16; 95% CI, 0.45–3). Two additional studies reported adverse events but were not included in this meta-analysis. In 2002, Baert et al5 reported only minor adverse events related to study medications but did not report them separately for the budesonide and placebo groups (viral infection [n ¼ 3], rash [n ¼ 2], hypertension [n ¼ 1], slight cushingoid face [n ¼ 3], and depression [n ¼ 1]). In 2009, Pardi et al11 (abstract only) stated that no signiﬁcant adverse effects occurred, but no numerical data were provided. This outcome is informed by low-quality evidence due to serious issues of inconsistency and imprecision. Finally, 2 trials reported data on the effect of budesonide on patients’ quality of life.15,21 One study showed an increase in quality

-,

No.

-

of life measured with the Gastrointestinal Quality of Life Index (GIQLI) of 23 points, although this increase was not statistically signiﬁcant (MD, 23; 95% CI, 7.49 to 53.5). One additional study reported quality of life using the SF-36 instrument. In 2009, Miehlke et al15 reported an increase in the mean change in the physical sum score of 3.5 points and in the mental sum score of 3.1 points. Serious issues of imprecision warrant a determination of moderate-quality evidence for this outcome. Interaction testing showed no difference in treatment response or other outcomes when comparing patients with CC or LC.

Budesonide versus mesalamine for inducing remission of MC. One trial provided evidence of the effect of budesonide (9 mg once daily [three 3-mg capsules]) compared with mesalamine (3 g once daily [2 sachets each containing 1.5 g mesalamine presented as a granule formulation; Salofalk]) (Table 7).16 Only 55 patients informed the outcome Q12 of clinical remission. Those receiving budesonide had an 82% increase in the probability of experiencing the outcome (RR, 1.82; 95% CI, 1.13–2.93) compared with those receiving mesalamine. This ﬁnding is supported by highquality evidence. For the outcome of histological response, patients receiving budesonide showed a 96% increase in the probability of experiencing the outcome (RR, 1.96; 95% CI, 1.14–3.36), which in relative terms corresponds to 427 more people per 1000 experiencing the beneﬁt. This ﬁnding is supported by high-quality evidence. Regarding adverse events, patients receiving budesonide had a lower risk of experiencing these compared with those receiving mesalamine; however, this difference was not statistically significant (RR, 0.69; 95% CI, 0.43–1.1). This ﬁnding is supported by moderate-quality evidence due to serious issues of imprecision. Quality of life was not reported. Interaction testing showed no difference in treatment response or other outcomes when comparing patients with CC or LC. Mesalamine versus no treatment for inducing remission of MC. One study reported on the effect of mesalamine versus placebo in 62 participants (Table 8).16 Patients receiving mesalamine (3 g once daily [2 sachets each containing 1.5 g presented as a granule formulation; Salofalk]) had a lower risk of experiencing clinical remission compared with those receiving placebo after 8 weeks; however, this difference was not statistically signiﬁcant (RR, 0.74; 95% CI, 0.44–1.24), and it is supported by moderatequality evidence due to serious imprecision. Regarding histological response, mesalamine seems to reduce the possibility of experiencing histological remission compared with placebo; however, this difference was not statistically signiﬁcant (RR, 0.89; 95% CI, 0.46–1.73). The quality of the evidence was determined as moderate for this outcome due to serious imprecision. For the outcome of adverse events, 68% of the patients experienced mild or minor adverse events compared with 54% in the control group; however, this difference was not statistically signiﬁcant (RR, 1.26; 95% CI, 0.84–1.88). This estimate is supported by moderate-quality evidence. No evidence for quality of life was reported. Mesalazine plus cholestyramine versus mesalazine for inducing remission of MC. One trial reported evidence on

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1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680

1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 -

2015

Table 5.Prednisolone Versus No Prednisolone for Inducing Remission of MC10 Quality assessment PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

No. of studies

Study design

No. of patients

Risk of Other bias Inconsistency Indirectness Imprecision considerations Prednisolone

Clinical response (follow-up: 2 wk) 1 Randomized Seriousa Not serious Not serious trials Histological response: not reported (follow-up: 2 wk) — — — — — Adverse events (follow-up: 2 wk) 1 Randomized Seriousa Not serious Not serious trials

Quality of life: not reported — — —

—

—

Very seriousb

None

2/9 (22.2%)

—

—

—

Seriousc

—

No treatment

Relative (95% CI)

0/3 (0.0%)

Not estimable

See comment Not estimable

None

—

Effect Absolute (95% CI)

Not estimable 4⃝⃝⃝ Critical Very low See comment

Typical corticosteroid-related side effects were common in the prednisolone group, but none were severe enough to cause patient withdrawal from the study (headache [n ¼ 5], abdominal pain [n ¼ 3], sleep disturbance [n ¼ 8], change of mood [n ¼ 4], weight gain [n ¼ 5]) —

—

—

Quality Importance

See comment

—

Important

44⃝⃝ Low

Critical

—

Critical

AGA Section

NOTE. Author(s): Alonso Carrasco-Labra, William Tremaine, and Darrell Pardi. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Prednisolone (50 mg once daily for 2 weeks and then 37.5 mg for one week). Comparison: No prednisolone (placebo). a High risk of bias due to selective outcome reporting (no histological response reported) and stopping early due to lack of effectiveness. It is unclear how the randomization scheme was created and the allocation sequence concealed. b The study included only 2 events, with zero events in the control group, which prevents estimation of absolute effect. Given that there were no events in the control group, the RR and absolute risk reduction could not be estimated. c The study included only 12 participants; 9 received prednisolone.

15

AGA SECTION

1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800

1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 AGA SECTION

16

Table 6.Budesonide Versus No Budesonide for Inducing Remission of MC5,6,11,14–16,21

No. of studies

Study design

No. of patients

Risk of Other bias Inconsistency Indirectness Imprecision considerations Budesonide No treatment

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Clinical response (follow-up: range, 6–8 wk) 6 Randomized Not Seriousa trials serious

Not serious

Not serious

None

Histological response (follow-up: range, 6–8 wk) 5 Randomized Not Seriousb trials serious

Not serious

Not serious

None

Not serious

None

Seriousg

None

Seriousk

None

Time to induce clinical remission (follow-up: 6 wk) 2 Randomized Seriousc Not serious Not serious trials Adverse events (induction therapy) (follow up: range, 6–8 wk) 3d,e Randomized Not Seriousf Not serious trials serious

Quality of life (follow-up: 6 wk; assessed with GIQLIh) Randomised Not Not serious Not serious 1i,j trials serious

Effect Relative (95% CI)

90/109 (82.6%) 41/109 (37.6%) RR, 2.52 (1.45–4.4)

65/85 (76.5%)

Absolute (95% CI)

572 more per 1000 444⃝ Critical (from 169 more Moderate to 1279 more)

23/82 (28.0%) RR, 2.5 421 more per 1000 444⃝ Important (1.56–3.99) (from 157 more Moderate to 839 more) 7–13 days (range, 2–30 days) to initial clinical remission

26/75 (34.7%)

17

Quality Importance

Pardi et al

Quality assessment

26/77 (33.8%) RR, 1.16 (0.45–3)

12

—

444⃝ Important Moderate

54 more per 1000 44⃝⃝ (from 186 Low fewer to 675 more) MD, 23 higher (7.49 lower to 53.49 higher)

Critical

444⃝ Critical Moderate

Gastroenterology Vol. -,

No. -

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Budesonide one 9-mg dose daily (three 3-mg capsules). Comparison: No budesonide (placebo). a Unexplained heterogeneity among included studies (c2 P value ¼ .007; I2 ¼ 68%). b Unexplained heterogeneity among included studies (c2 P value ¼ .17; I2 ¼ 38%). c High risk of bias due to selective outcome reporting. No measure of variability was reported. d Two additional studies reported adverse events but were not included in this meta-analysis. Baert et al5 (2002) reported only minor adverse events related to study medications but did not report them separately for the budesonide and placebo groups (viral infection [n ¼ 3], rash [n ¼ 2], hypertension [n ¼ 1], slight cushingoid face [n ¼ 3], depression [n ¼ 1]). Pardi et al11 (2009, abstract) only describe that no signiﬁcant side effects occurred; no numerical data were provided. e The most common adverse events listed in the studies were nausea, headache, abdominal pain, and skin rash. f Unexplained heterogeneity among included studies (c2 P value ¼ .08; I2 ¼ 60%). g The lower and upper boundaries of the CI suggest both large beneﬁt and harm. h The GIQLI score consists of 4 dimensions (symptoms, physical functioning, emotional functioning, and social functioning). The overall score ranges from 0 to 144 (the higher the score, the better the quality of life). Healthy volunteers have been reported to have a mean score of 121–126 using the GIQLI. These values compare with previously reported mean scores of 104 in patients with anal ﬁssures, 94 in those with severe chronic constipation, 93 in those with fecal incontinence, and 87 in those with gastroesophageal reﬂux disease requiring surgery.31 i One additional study reported quality of life using the SF-36 instrument. Miehlke et al15 (2009) reported an increase in the mean of the change for the physical sum score of 3.5 points and for the mental sum score of 3.1 points. j There was a large difference in baseline quality of life between patients in the budesonide arm (67 points) and those in the control group (86 points). k The lower and upper boundaries of the CI suggest small harm and large beneﬁt.

1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917 1918 1919 1920

1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 -

2015

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Table 7.Budesonide Versus Mesalamine for Inducing Remission of MC16 Quality assessment No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations Budesonide Mesalamine

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance

Clinical response (follow up: 8 wk) 1 Randomized Not serious Not serious trials

Not serious

Not serious

None

24/30 (80.0%) 11/25 (44.0%) RR, 1.82 361 more per 4444 Critical (1.13–2.93) 1000 (from High 57 more to 849 more)

Histological response (follow-up: 8 wk) 1 Randomized Not serious Not serious trials

Not serious

Not serious

None

20/23 (87.0%)

Adverse events (induction therapy) (follow-up: 8 wk) 1 Randomized Not serious Not serious trials

Not serious

Seriousa

None

14/30 (46.7%) 17/25 (68.0%) RR, 0.69 (0.43–1.1)

Quality of life: not reported — —

—

—

—

—

—

—

8/18 (44.4%) RR, 1.96 427 more per 4444 Important (1.14–3.36) 1000 (from High 62 more to 1049 more)

See comment Not estimable

211 fewer per 444⃝ Critical 1000 (from Moderate 68 more to 388 fewer) See comment

—

Critical

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Budesonide one 9-mg dose daily (three 3-mg capsules). Comparison: Mesalamine 3 g once daily (2 sachets each containing 1.5 g mesalamine presented as a granule formulation; Salofalk). a The CI includes both potential beneﬁt and large harm.

AGA Section 17

AGA SECTION

1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040

2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 AGA SECTION

18 Pardi et al

Table 8.Mesalamine Versus No Mesalamine for Inducing Remission of MC16 PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Quality assessment No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations Mesalamine No treatment

Clinical response (follow-up: 8 wk) 1 Randomized Not serious Not serious trials

Not serious

Seriousa

None

Histological response (follow-up: 8 wk) 1 Randomized Not serious Not serious trials

Not serious

Seriousa

None

Adverse events (induction therapy) (follow-up: 8 wk) 1 Randomized Not serious Not serious Not serious trials

Seriousa

None

Quality of life: not reported — — —

—

—

—

—

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance

11/25 (44.0%) 22/37 (59.5%) RR, 0.74 155 fewer per 444⃝ Critical (0.44–1.24) 1000 (from Moderate 143 more to 333 fewer) 8/18 (44.4%) 11/22 (50.0%) RR, 0.89 55 fewer per (0.46–1.73) 1000 (from 270 fewer to 365 more)

444⃝ Important Moderate

17/25 (68.0%) 20/37 (54.1%) RR, 1.26 141 more per 444⃝ Critical (0.84– 1.88) 1000 (from Moderate 86 fewer to 476 more) —

See comment Not estimable

See comment

—

Critical

Gastroenterology Vol.

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Mesalamine (mesalamine 3 g once daily, 2 sachets each containing 1.5 g mesalamine presented as a granule formulation; Salofalk). Comparison: No mesalamine (placebo). a Small number of events. The CI suggests both important beneﬁt and large harm.

-,

No. -

2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160

2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 -

2015

Table 9.Mesalazine Plus Cholestyramine Versus Mesalazine for Inducing Remission of MC22 PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Quality assessment No. of studies

Study design

No. of patients

Risk of Other Mesalazine þ bias Inconsistency Indirectness Imprecision considerations cholestyramine

Mesalazine

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance

Clinical response (follow-up: 6 mo) 1 Randomized Seriousa Not serious trials

Not serious

Seriousb

None

30/33 (90.9%)

26/31 (83.9%) RR, 1.09 (0.89–1.32)

75 more per 1000 (from 92 fewer to 268 more)

Histological response (follow-up: 6 mo) 1 Randomized Seriousa Not serious trials

Not serious

Seriousb

None

26/31 (83.9%)

30/33 (90.9%) RR, 0.92 (0.76–1.12)

73 fewer per 44⃝⃝ 1000 (from Low 109 more to 218 fewer)

Adverse events (induction therapy) (follow-up: 6 mo) 1 Randomized Seriousa Not serious Not serious trials

Seriousb

None

2/33 (6.1%)c

—

—

Quality of life: not reported — — —

—

—

—

0/31 (0.0%)

RR, 4.71 0 fewer per (0.23–94.31) 1000 (from 0 fewer to 0 fewer)d

See comment Not estimable

See comment

44⃝⃝ Low

Critical

Important

44⃝⃝ Low

Critical

—

Critical

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Mesalazine plus cholestyramine (mesalazine 800 mg, one capsule after breakfast, lunch, and dinner [2.4 g daily], and cholestyramine 4 g after dinner for 6 months). Comparison: Mesalazine (800 mg, one capsule after breakfast, lunch, and dinner [2.4 g daily]). a Neither participants nor personnel or researchers were blinded during the study. It is unclear how the random allocation was concealed. b The CI includes both appreciable harm and beneﬁt. c Two patients in the mesalazine plus cholestyramine group experienced nausea. d Absolute effect not estimable due to zero events in the control group. AGA Section 19

AGA SECTION

2221 2222 2223 2224 2225 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 2279 2280

20

AGA SECTION

2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305Q13 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340

Pardi et al

Gastroenterology Vol.

the effect of cholestyramine in addition to mesalazine (mesalazine 800 mg, one capsule after breakfast, lunch, and dinner [2.4 g daily], and cholestyramine 4 g after dinner for 6 months) compared with mesalazine alone (mesalazine 800 mg, one capsule after breakfast, lunch, and dinner [2.4 g daily]) (Table 9).22 In this trial, which included 64 patients, those receiving mesalazine plus cholestyramine experienced a 9% increased probability of clinical remission when comparing with those receiving mesalazine alone (RR, 1.09; 95% CI, 0.89–1.32) after 6 months of follow-up. Regarding histological response, the effect was the opposite, showing an 8% reduction in the probability of experiencing this outcome for patients receiving combination therapy (RR, 0.92; 95% CI, 0.76–1.12). Finally, participants receiving cholestyramine plus mesalazine experienced 6% more adverse events compared with those receiving mesalazine only (RR, 4.71; 95% CI, 0.23–94.31). None of the outcomes show statistically signiﬁcant differences between the 2 groups. In addition, the quality of evidence was assessed as low for all outcomes due to serious imprecision. The outcome of quality of life was not reported for this comparison. There are no clinical trials assessing the efﬁcacy of cholestyramine or other bile acid–binding medication alone.

Boswellia serrata versus treatment for inducing remission of MC. One trial reported data on 31 patients for the effect of Boswellia serrata, 400 mg per capsule 3 times per day (21.2 mg 11-keto-b-boswellia acid, 27.3 mg a-boswellia acid, 50.9 mg b-boswellia acid, 11.3 mg acetyl-11keto-b- boswellia acid, 9.8 mg acetyl-a-boswellia acid, and 28.7 mg acetyl-b-boswellia acid), versus placebo (Table 10).13 Participants receiving Boswellia serrata showed a 64% increase in the probability of experiencing a clinical response after 6 weeks (RR, 1.64; 95% CI, 0.60–4.49); however, this difference was not statistically signiﬁcant. This ﬁnding is supported by moderate-quality evidence due to serious imprecision. For the outcome of histological response, the investigators only declared that there was no statistically signiﬁcant difference between groups, supported by moderate-quality evidence due to serious risk of bias. Participants receiving Boswellia serrata experienced more adverse events compared with those in the placebo group; however, this difference was not statistically signiﬁcant (RR, 1.88; 95% CI, 0.19–18.6). Low conﬁdence in the estimates of effect was determined for this outcome due to very serious issues of imprecision. Finally, the investigators reported that at the end of 6 weeks of therapy, there were no signiﬁcant changes in quality of life scores in the Boswellia serrata or placebo groups when comparing baseline with posttreatment or between groups after treatment was completed. No numerical data were provided for this outcome. Serious risk of bias due to selective outcome reporting led to a determination of moderate-quality evidence. Probiotics versus no treatment for inducing remission of MC. One trial, which included 29 participants, informed about the effect of a probiotic (AB-Cap-10, a mixture of Lactobacillus acidophilus strain LA-5 and Biﬁdobacterium animalis subsp lactis strain BB-12) compared with placebo for inducing remission of MC (Table 11).12 The use of the

-,

No.

-

probiotic increased the probability of experiencing clinical remission after 12 weeks by 129% (RR, 2.29; 95% CI, 0.32–16.13); however, this difference was not statistically signiﬁcant. These ﬁndings are supported by moderatequality evidence. Regarding histological response, no numerical data were reported, but the investigators declared “no differences in histopathological changes between or within groups were observed after 12 weeks.” This ﬁnding is supported by low-quality evidence. For the outcome of adverse events, the probiotic group experienced worsening of diarrhea, abdominal pain and constipation, stomach burning, nausea, and ﬂatulence after 12 weeks of follow-up; these ﬁndings are supported by moderate-quality evidence. Finally, quality of life was assessed using the Short Inﬂammatory Bowel Disease Questionnaire (SIBDQ) after 12 weeks. An increase in the instrument score of 3% (no information on variability for this estimate was reported) was observed. This ﬁnding is supported by low-quality evidence.

Beclomethasone versus mesalazine for inducing remission of MC. One trial, which included 33 participants, reported data for this comparison.7 Two doses of beclomethasone dipropionate, 5 mg/day and 10 mg/day, were compared with mesalazine 2.4 mg/day. Although the interaction test showed no statistically signiﬁcant differences between the 2 doses, the results are reported separately for convenience. For both doses, beclomethasone showed a reduction in the probability of experiencing clinical remission of 4% for the 5-mg dose and 2% for the 10-mg dose when compared with mesalazine after 8 weeks. Regarding the outcome of adverse events, the authors only reported that beclomethasone and mesalazine were well tolerated with no serious side effects (no numerical data were provided). Low conﬁdence in estimates of effect was determined for all these outcomes due to serious imprecision and very serious risk of bias. Neither histological response nor quality of life were reported (Table 12). Question 3. In patients successfully treated for MC (either LC or CC) and in remission of symptoms, which treatments are effective and safe for maintaining clinical remission of the disease, measured as maintenance of clinical response, maintenance of histological response, time to relapse, quality of life, and adverse events?

Budesonide versus no treatment for maintaining remission of MC. Three randomized controlled trials, including a total of 80 participants, reported data for this comparison (Table 13).8,9,23 Two doses of budesonide were studied to maintain clinical remission: 6 mg once a day (two 3-mg capsules for 6 months)8,23 and 4.5 mg/day (two 3-mg capsules every other day alternating with one 3-mg capsule every other day for 12 months).9 The 6-mg dose reduced the risk of clinical relapse at 6 months by 66% (RR, 0.34; 95% CI, 0.19–0.6), which in absolute terms means that 495 relapse events can be avoided per 1000 people. This ﬁnding is supported by high-quality evidence. The 4.5-mg dose also showed a reduction in the risk of experiencing a relapse of 54% (RR, 0.46; 95% CI, 0.31–0.69) compared with placebo after 13 months of

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

2341 2342 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 2396 2397 2398 2399 2400

2401 2402 2403 2404 2405 2406 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429 2430 2431 2432 2433 2434 2435 2436 2437 2438 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 2460 No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Clinical response (follow-up: 6 wk) 1 Randomized Not Not serious trials serious

Not serious

Seriousa

None

Histological response (follow-up: 6 wk) 1 Randomized Seriousb Not serious trials

Not serious

Not serious

None

Histological response (follow-up: 6 wk) 1c Randomized Not Not serious trials serious

Not serious

Very seriousd

None

Not serious

None

Quality of life (follow-up: 6 wk; assessed with: SF-36 instrument) 1 Randomized Seriousb Not serious Not serious trials

Boswellia serrata 7/16 (43.8%)

No treatment

2015

Quality assessment

-

Table 10.Boswellia serrata Versus No Boswellia for Inducing Remission of MC13 Effect Relative (95% CI)

Absolute (95% CI)

4/15 (26.7%) RR, 1.64 171 more per (0.60–4.49) 1000 (from 121 fewer to 512 more)

Quality Importance 444⃝ Critical Moderate

Slight reduction in the thickness of 444⃝ Important the subepithelial collagen band Moderate and inﬂammation score in both the Boswellia serrata and placebo groups at the end of 6 weeks of therapy, but no statistically signiﬁcant difference compared with baseline or between the groups; no numerical data were provided 2/16 (12.5%)

1/15 (6.7%)

RR, 1.88 59 more per 1000 44⃝⃝ (0.19–18.6) (from 54 fewer Low to 1173 more)

Critical

At the end of 6 weeks of therapy, 444⃝ Critical Moderate there were no signiﬁcant changes in quality of life scores in either the Boswellia serrata or placebo groups compared with baseline or between groups; no numerical data were provided

AGA Section

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Boswellia serrata 400 mg per capsule 3 times per day (21.2 mg 11-ketob-boswellia acid, 27.3 mg a-boswellia acid, 50.9 mg b-boswellia acid, 11.3 mg acetyl-11-keto-b-boswellia acid, 9.8 mg acetyl-a-boswellia acid, and 28.7 mg acetylb-boswellia acid). Comparison: No Boswellia serrata (placebo). a The study included only 11 events. The lower and upper limits of the CI suggest both appreciable harm and important beneﬁt. b High risk of bias. No numerical data were reported. The investigators declared that there was no statistically signiﬁcant difference compared with baseline or between groups. c Adverse events included hypoglycemia, dizziness, anorexia, and bacterial enteritis. d Only 3 events are reported in the study. The CI includes appreciable beneﬁt and harm in both extremes and for relative and absolute effects.

21

AGA SECTION

2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 2506 2507 2508 2509 2510 2511 2512 2513 2514 2515 2516 2517 2518 2519 2520

2521 2522 2523 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 2534 2535 2536 2537 2538 2539 2540 2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2551 2552 2553 2554 2555 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566 2567 2568 2569 2570 2571 2572 2573 2574 2575 2576 2577 2578 2579 2580 AGA SECTION

22

Table 11.Probiotics Versus No Probiotics for Inducing Remission of MC12

No. of studies

Study design

Risk of bias

No. of patients

Effect

Other Relative (95% Inconsistency Indirectness Imprecision considerations Probiotics No treatment CI)

Absolute (95% CI)

Quality Importance

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Clinical response (follow-up: 12 wk) 1 Randomized Not serious Not serious trials

Not serious

Seriousa

None

Histological response (follow-up: 12 wk) 1 Randomized Seriousb Not serious trials

Not serious

Seriousc

None

No differences in 44⃝⃝ histopathological changes Low between or within groups were observed at 12 weeks; numerical data were not reported

Adverse events (induction therapy) (follow-up: 12 wk) 1 Randomized Not serious Not serious Not serious trials

Seriousc

None

444⃝ Critical In the probiotic group, Moderate worsening of diarrhea (n ¼ 1), abdominal pain and constipation (n ¼ 2), stomach burn (n ¼ 1), nausea (n ¼ 1), and ﬂatulence (n ¼ 1) were reported; in the placebo group, 4 patients had nausea; in 1 patient, development of constipation and abdominal pain led to discontinuation of study drug for 6 wk

Quality of life (follow-up: 12 wk; assessed with the SIBDQ) 1 Randomized Serious Not seriousd Not serious trials

Seriousc

None

6/21 (28.6%)

21

1/8 (12.5%)

8

Pardi et al

Quality assessment

RR, 2.29 161 more per 444⃝ Critical (0.32–16.13) 1000 (from Moderate 85 fewer to 1891 more)

—

MD, 3 higher 44⃝⃝ (0 higher to Low 0 higher)

Important

Critical

Gastroenterology Vol. -,

No.

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Probiotics (AB-Cap-10, a mixture of L acidophilus strain LA-5 and B animalis subsp lactis strain BB-12). One capsule contained 0.5 1010 colony-forming units (CFU) of each bacterium, leading to a total delivery of 1 1010 CFU in each capsule. ABCap-10 was given as 2 capsules twice daily, resulting in a total delivery of 4 1010 CFU daily. Comparison: No probiotics (placebo). a The study included only 7 events. Both limits of the CI show an important harm and a large beneﬁt. b High risk of bias due to selective outcome reporting. No numerical data regarding histological response were reported. c The study included only 29 participants and 7 events. d High risk of bias due to selective outcome reporting. Only ranges were reported as a measure of variability between groups.

-

2581 2582 2583 2584 2585 2586 2587 2588 2589 2590 2591 2592 2593 2594 2595 2596 2597 2598 2599 2600 2601 2602 2603 2604 2605 2606 2607 2608 2609 2610 2611 2612 2613 2614 2615 2616 2617 2618 2619 2620 2621 2622 2623 2624 2625 2626 2627 2628 2629 2630 2631 2632 2633 2634 2635 2636 2637 2638 2639 2640

2641 2642 2643 2644 2645 2646 2647 2648 2649 2650 2651 2652 2653 2654 2655 2656 2657 2658 2659 2660 2661 2662 2663 2664 2665 2666 2667 2668 2669 2670 2671 2672 2673 2674 2675 2676 2677 2678 2679 2680 2681 2682 2683 2684 2685 2686 2687 2688 2689 2690 2691 2692 2693 2694 2695 2696 2697 2698 2699 2700 -

2015

Table 12.Beclomethasone Versus Mesalazine for Inducing Remission of MC7 Quality assessment PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations Beclomethasone Mesalazine

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance

Clinical response: beclomethasone 5 mg (follow-up: 8 wk) 1 Randomized Seriousa Not serious Not serious trials

Seriousb

None

15/18 (83.3%)

13/15 (86.7%) RR, 0.96 35 fewer per 44⃝⃝ (0.72–1.28)c 1000 (from Low 243 fewer to 243 more)

Critical

Clinical response: beclomethasone 10 mg (follow-up: 8 wk) 1 Randomized Seriousa Not serious Not serious trials

Seriousb

None

11/13 (84.6%)

13/15 (86.7%) RR, 0.98 17 fewer per 44⃝⃝ (0.72–1.32)c 1000 (from Low 243 fewer to 277 more)

Important

—

—

Histological response: not reported — — — — — Adverse events (induction therapy) (follow-up: 8 wk) 1 Randomized Very Not serious Not serious trials seriousa

Quality of life: not reported — — —

—

—

— Not serious

—

None

—

See comment Not estimable

See comment

Both beclomethasone and mesalazine were well tolerated with no serious side effects; no numerical data were provided —

See comment Not estimable

See comment

— 44⃝⃝ Low

—

Critical Critical

Critical

AGA Section

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Beclomethasone dipropionate 5 mg/day and 10 mg/day. Comparison: Mesalazine 2.4 mg/day. a Most of the risk of bias domains assessed were evaluated as unclear. High risk of bias due to selective outcome reporting. b Small number of events. The CI includes both appreciable harm and beneﬁt. c Test for interaction showed no differences between these 2 doses.

23

AGA SECTION

2701 2702 2703 2704 2705 2706 2707 2708 2709 2710 2711 2712 2713 2714 2715 2716 2717 2718 2719 2720 2721 2722 2723 2724 2725 2726 2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 2737 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 2759 2760

2761 2762 2763 2764 2765 2766 2767 2768 2769 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 2780 2781 2782 2783 2784 2785 2786 2787 2788 2789 2790 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 2802 2803 2804 2805 2806 2807 2808 2809 2810 2811 2812 2813 2814 2815 2816 2817 2818 2819 2820 AGA SECTION

No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations Budesonide No treatment

Effect Relative (95% CI)

Absolute (95% CI)

Pardi et al

Quality assessment

24

Table 13.Budesonide Versus No Budesonide for Maintaining Remission of MC8,9,23

Quality Importance

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Maintenance of clinical response: budesonide 6 mg (follow-up: 6 mo) 2 Randomized Not serious Not serious Not serious Not serious trials

None

10/40 (25.0%) 30/40 (75.0%) RR, 0.34 (0.19–0.6)a

495 fewer per 1000 (from 300 fewer to 608 fewer)

4444 Critical High

Maintenance of clinical response: budesonide 3 mg (follow-up: 13 mo) 1 Randomized Not serious Not serious Not serious Not serious trials

None

17/44 (38.6%) 40/48 (83.3%) RR, 0.46 450 fewer per (0.31–0.69)a 1000 (from 258 fewer to 575 fewer)

4444 Critical High

Maintenance of histological response: budesonide 6 mg (follow-up: 6 mo) 2 Randomized Not serious Not serious Not serious Not serious trials

None

21/40 (52.5%) 34/40 (85.0%) Odds ratio, 0.21 307 fewer per 4444 Important (0.08–0.54) 1000 (from High 96 fewer to 538 fewer)

Time to relapse during maintenance therapy (follow-up: 6 mo; assessed with days) 1 Randomized Not serious Not serious Not serious Seriousb trials

None

17

15

—

MD, 161 higher 444⃝ Critical (7.83 higher Moderate to 314.17 higher)

Time to relapse after maintenance therapy (follow-up: 6 mo; assessed with days) 1c Randomized Not serious Not serious Not serious Seriousd trials

None

17

15

—

MD, 1 higher (4.1 lower to 6.1 higher)

Adverse events (maintenance therapy): budesonide 6 mg (follow-up: 6 mo) 2e Randomized Not serious Not serious Not serious Seriousf trials

None

Adverse events (maintenance therapy): budesonide 3 mg (follow-up: 13 mo) 1g Randomized Not serious Not serious Not serious Seriousf trials

None

Q28

13/40 (32.5%) 16/40 (40.0%) RR, 0.81 (0.45–1.47)

5/48 (10.4%) RR, 1.53 (0.52–4.46)

444⃝ Critical Moderate

76 fewer per 444⃝ Critical 1000 (from Moderate 188 more to 220 fewer) 55 more per 444⃝ Critical 1000 (from Moderate 50 fewer to 360 more)

Gastroenterology Vol.

7/44 (15.9%)

Q29

-,

No. -

2821 2822 2823 2824 2825 2826 2827 2828 2829 2830 2831 2832 2833 2834 2835 2836 2837 2838 2839 2840 2841 2842 2843 2844 2845 2846 2847 2848 2849 2850 2851 2852 2853 2854 2855 2856 2857 2858 2859 2860 2861 2862 2863 2864 2865 2866 2867 2868 2869 2870 2871 2872 2873 2874 2875 2876 2877 2878 2879 2880

2881 2882 2883 2884 2885 2886 2887 2888 2889 2890 2891 2892 2893 2894 2895 2896 2897 2898 2899 2900 2901 2902 2903 2904 2905 2906 2907 2908 2909 2910 2911 2912 2913 2914 2915 2916 2917 2918 2919 2920 2921 2922 2923 2924 2925 2926 2927 2928 2929 2930 2931 2932 2933 2934 2935 2936 2937 2938 2939 2940 -

Table 13. Continued

No. of studies

Study design

Risk of bias

No. of patients

Other Inconsistency Indirectness Imprecision considerations Budesonide No treatment

Quality of life (follow-up: range, 6–13 mo; assessed with SF-36, SIBDQ, and the Short Health Scale) Not serious Not serious Not serious None 2 Randomized Serioush trials

2015

Quality assessment

Effect Relative (95% CI)

Absolute (95% CI)

Quality Importance

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

444⃝ Critical Miehlke et al8 (2008): Physical and mental SF-36 scores in Moderate patients receiving budesonide increased to levels similar to those observed in “normal” subjects after induction, and these changes were maintained during maintenance therapy; no numerical data were reported Munch et al9 (2014): Quality of life was unchanged after 1 y in the budesonide group but showed clinically relevant deterioration in the placebo group; no numerical data were provided

AGA Section

NOTE. Date: December 5, 2014. Question: In patients with MC (either LC or CC), which treatments are effective and safe for inducing remission of the disease, measured as clinical response, histological response, quality of life, and adverse events? Intervention: Miehlke et al8 (2008) and Bonderup et al23 (2009): budesonide 6 mg once a day (two 3-mg capsules for 6 months); Munch et al9 (2014): budesonide 3 mg (2 capsules every other day and 1 capsule every other day; average 4.5 mg/day for 12 months). Comparison: No budesonide (placebo). a Test for interaction between the 2 doses of budesonide showed no statistically signiﬁcant differences. b The CI includes negligible beneﬁt and a large beneﬁt. c Munch et al9 (2014), not included in the meta-analysis, reported a mean of 40 days to relapse after maintenance therapy (range, 27–57 days). d Unexplained heterogeneity between the 2 studies reporting this outcome. Results differ considerably. e Among budesonide recipients, Miehlke et al8 (2008) reported adverse events, including headache (2), urinary infection (1), respiratory infection (1), back pain (1), abdominal pain (1), increased body weight (1), and hypertension (1). Among patients who withdrew from the study, adverse events included dizziness (1), sleep disturbance (1), muscle pain (1), gastric ulcer (1), and skin erythema (1). Bonderup et al23 (2009) reported worsening of diabetes (2), dyspepsia (1), bruising (1), and subarachnoid hemorrhage (1). The latter adverse event, which occurred after 22 weeks of active treatment (ie, 6 weeks of induction plus 16 weeks of maintenance therapy), was considered to be serious and the patient was withdrawn from the study. f Limits of the CI include both appreciable beneﬁt and large harm. g The investigators did not report adverse events in detail (described as an adverse drug reaction). h High risk of bias due to selective outcome reporting. No numerical data were provided.

25

AGA SECTION

2941 2942 2943 2944 2945 2946 2947 2948 2949 2950 2951 2952 2953 2954 2955 2956 2957 2958 2959 2960 2961 2962 2963 2964 2965 2966 2967 2968 2969 2970 2971 2972 2973 2974 2975 2976 2977 2978 2979 2980 2981 2982 2983 2984 2985 2986 2987 2988 2989 2990 2991 2992 2993 2994 2995 2996 2997 2998 2999 3000

26

AGA SECTION

3001 3002 3003 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 3015 3016 3017 3018 3019 3020 3021 3022 3023 3024 Q14 3025 3026 3027 3028 3029 Q15 3030 3031 3032 3033 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 3047 3048 3049 3050 3051 3052 3053 3054 3055 3056 3057 3058 3059 3060

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follow-up. In absolute terms, 450 relapse events can be avoided per 1000 people. The quality of the evidence for this outcome was also assessed as high. Regarding maintenance of histological response, the meta-analysis showed that budesonide 6 mg reduces the risk of histological relapse by 79% (RR, 0.21; 95% CI, 0.08–0.54). In absolute terms, this means that 307 histological relapse events can be avoided per 1000 people. The quality of the evidence for this outcome was also assessed as high. After 6 months of follow-up, the time to relapse during maintenance therapy was on average 161 days longer for the patients in the budesonide group compared with those receiving placebo (MD, 161; 95% CI, 7.8–314.2). This ﬁnding is supported by moderate-quality evidence. The time to relapse after maintenance therapy was completed (without medication) was 1 day longer in patients receiving budesonide compared with placebo (MD, 1; 95% CI, 4.1 to 6.1); however, this difference was not statistically signiﬁcant. The 2014 study by Munch et al,9 which was included in the meta-analysis, reported a mean of 40 days to relapse after maintenance therapy (range, 27–57 days). This outcome was assessed as having moderate-quality evidence due to serious inconsistency. Adverse events were also analyzed separately for both doses to facilitate decision making. For both the 6-mg and 3-mg doses of budesonide, there were no statistically signiﬁcant differences between the 2 groups. However, there is no evidence regarding long-term toxicity in patients treated with budesonide for more than 6 months. It has been recommended that these patients be monitored for corticosteroid-related adverse effects.24 Quality of life was measured in 2 trials. Miehlke et al8 reported that physical and mental SF-36 scores in patients receiving budesonide increased to levels similar to those observed in “normal” subjects after induction, and these changes remained stable during maintenance therapy. However, no numerical data were reported. Munch et al9 reported that quality of life did not change after 1 year of treatment with budesonide; however, participants receiving placebo showed a clinically relevant deterioration. No numerical data were provided. The quality of the evidence for this outcome was assessed as moderate due to serious risk of bias issues.

Discussion

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No.

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“Was the study affected by selective outcome reporting?” In this case, 8 of 15 studies were classiﬁed as “high risk of bias” due to the fact that the investigators did not provide numerical data for their results but only stated a lack of statistical signiﬁcance.

Quality of the Evidence The quality of the evidence ranged from high to very low across outcomes. The main reasons for downgrading were issues of serious imprecision due to the small number of participants per trial and risk of bias mainly due to selective outcome reporting. Investigators tended to avoid reporting numerical data when the trial showed results that were not statistically signiﬁcant, making it impossible to include these data in the meta-analyses.

Comparison With Previous Systematic Reviews To our knowledge, this is the most updated systematic review on interventions to treat MC. Previous reviews included fewer studies and had less precise results but came to similar conclusions regarding the role of budesonide as the most studied medication for treating Q16 MC.26–30 The inclusion of 3 new randomized controlled trials9,15,16 with 218 patients increased the number of participants compared with the previous reviews such that imprecision is no longer an issue for many outcomes. In particular, this review increased the certainty about the role of budesonide for both inducing and maintaining clinical remission.

Strengths and Limitations of This Review The strengths of this review include the comprehensive search strategy that included multiple databases. In addition, the absence of restriction by language or status of publication allowed us to include key abstracts from conferences and other meetings that have not been published in full version. Screening for articles was conducted independently and in duplicate, while a second reviewer checked the data extraction process. A limitation was that, for many interventions identiﬁed, serious imprecision did not allow more deﬁnitive conclusions. In general, the trials included few participants and events that affected the precision of the CIs.

Summary of the Main Results

Conclusions

This review summarizes the best available evidence related to the medical management of MC and clinical features to diagnose celiac disease in this type of patient. A total of 17 primary studies contributed to the body of evidence. The medical interventions identiﬁed covered both induction and maintenance of remission of MC. The most promising intervention identiﬁed for both purposes was budesonide, supported by moderate- to high-quality evidence. The results for other interventions were too imprecise to draw meaningful conclusions. The selection criteria and outcome deﬁnition were consistent across trials. The main risk of bias identiﬁed was for the question

Implications for clinical practice. The most important ﬁnding of this review for clinical practice is the effectiveness of budesonide and the role of this medication for inducing and maintaining remission of MC. Implications for research. Multicenter, high-quality, randomized controlled trials of new treatments should be conducted, particularly of noncorticosteroid medications and comparing budesonide with other interventions. More interventions to manage MC should be investigated, particularly to identify effective alternatives to budesonide. Additional research into the mechanism(s) and natural history of MC is warranted.

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3061 3062 3063 3064 3065 3066 3067 3068 3069 3070 3071 3072 3073 3074 3075 3076 3077 3078 3079 3080 3081 3082 3083 3084 3085 3086 3087 3088 3089 3090 3091 3092 3093 3094 3095 3096 3097 3098 3099 3100 3101 3102 3103 3104 3105 3106 3107 3108 3109 3110 3111 3112 3113 3114 3115 3116 3117 3118 3119 3120

3121 3122 3123 3124 3125 3126 3127 3128 3129 3130 3131 3132 3133 3134 3135 3136Q17 3137 3138 3139 3140 3141 3142Q18 3143 3144 3145 3146 3147 3148 3149 3150 3151 3152 3153 3154 3155 3156 3157 3158Q19 3159 3160 3161 3162 3163 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 3174 3175 3176 3177 3178 3179 3180

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Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2015.11.006.

13.

14.

References 1. Guyatt GH, Oxman AD, Kunz R, et al. What is “quality of evidence” and why is it important to clinicians? BMJ 2008;336:995–998. 2. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT GS, ed. Cochrane handbook for systematic reviews of interventions, version 5.1.0 (updated March 2011) 2011. The Cochrane Collaboration, 2011. www.cochranehandbook.org. 3. Reitsma JB, Rutjes AWS, Whiting P, et al. Chapter 9: Assessing methodological quality. In: Deeks JJ BP, Gatsonis C, eds. Cochrane handbook for systematic reviews of diagnostic test accuracy, version 1.0.0 2009. The Cochrane Collaboration, 2009. http://srdta. cochrane.org/. 4. Schunemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008;336: 1106–1110. 5. Baert F, Schmit A, D’Haens G, et al. Budesonide in collagenous colitis: a double-blind placebo-controlled trial with histologic follow-up. Gastroenterology 2002; 122:20–25. 6. Bonderup OK, Hansen JB, Birket-Smith L, et al. Budesonide treatment of collagenous colitis: a randomised, double blind, placebo controlled trial with morphometric analysis. Gut 2003;52:248–251. 7. Latella G, Angelucci E, Tsolaki A, et al. Beclometasone dipropionate and mesalazine are equally effective in the treatment of lymphocytic colitis. Dig Liver Dis 2010; 42:S87. 8. Miehlke S, Madisch A, Bethke B, et al. Oral budesonide for maintenance treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2008;135:1510–1516. 9. Munch A, Bohr J, Miehlke S, et al. Clinical remisison and quality of life in collagenous colitis: a one-year, randomised, placebo-controlled study with low-dose budesonide (BUC-63/ COC) (abstr). Gastroenterology 2014; 146(suppl 1):S-586. 10. Munck LK, Kjeldsen J, Philipsen E, et al. Incomplete remission with short-term prednisolone treatment in collagenous colitis: a randomized study. Scand J Gastroenterol 2003;38:606–610. 11. Pardi DS, Loftus EV, Tremaine WJ, et al. A randomized, double-blind, placebo-controlled trial of budesonide for the treatment of active lymphocytic colitis (abstr). Gastroenterology 2009;138(suppl 1): A519–A520. 12. Wildt S, Munck LK, Vinter-Jensen L, et al. Probiotic treatment of collagenous colitis: a randomized, doubleblind, placebo-controlled trial with Lactobacillus

15.

16.

17.

18.

19.

20.

21.

22.

23.

24. 25.

26.

27.

28.

27

acidophilus and Biﬁdobacterium animalis subsp. lactis. Inﬂamm Bowel Dis 2006;12:395–401. Madisch A, Miehlke S, Eichele O, et al. Boswellia serrata extract for the treatment of collagenous colitis. A doubleblind, randomized, placebo-controlled, multicenter trial. Int J Colorectal Dis 2007;22:1445–1451. Miehlke S, Heymer P, Bethke B, et al. Budesonide treatment for collagenous colitis: a randomized, doubleblind, placebo-controlled, multicenter trial. Gastroenterology 2002;123:978–984. Miehlke S, Madisch A, Karimi D, et al. Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-controlled study. Gastroenterology 2009;136:2092–2100. Miehlke S, Madisch A, Kupcinskas L, et al. Budesonide is more effective than mesalamine or placebo in short-term treatment of collagenous colitis. Gastroenterology 2014; 146:1222–1230.e2. Freeman HJ. Perinuclear antineutrophil cytoplasmic antibodies in collagenous or lymphocytic colitis with or without celiac disease. Can J Gastroenterol 1997; 11:417–420. Freeman HJ. Collagenous colitis as the presenting feature of biopsy-deﬁned celiac disease. J Clin Gastroenterol 2004;38:664–668. Fine KD, Ogunji F, Lee EL, et al. Randomized, doubleblind, placebo-controlled trial of bismuth subsalicylate for microscopic colitis (abstr). Gastroenterology 1999; 116(suppl 1):A880. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses. In: J.P.T. H, Green S, eds. Cochrane handbook for systematic reviews of interventions, version 5.1.0 (updated March 2011): The Cochrane Collaboration, 2011. www.cochranehandbook.org. Madisch A, Heymer P, Voss C, et al. Oral budesonide therapy improves quality of life in patients with collagenous colitis. Int J Colorectal Dis 2005;20:312–316. Calabrese C, Fabbri A, Areni A, et al. Mesalazine with or without cholestyramine in the treatment of microscopic colitis: randomized controlled trial. J Gastroenterol Hepatol 2007;22:809–814. Bonderup OK, Hansen JB, Teglbjaerg PS, et al. Longterm budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial. Gut 2009;58:68–72. Pardi DS. After budesonide, what next for CC? Gut 2009; 58:3–4. Armes J, Gee DC, Macrae FA, et al. Collagenous colitis: jejunal and colorectal pathology. J Clin Pathol 1992; 45:784–787. Feyen B, Wall GC, Finnerty EP, et al. Meta-analysis: budesonide treatment for collagenous colitis. Aliment Pharmacol Ther 2004;20:745–749. Nyhlin N, Bohr J, Eriksson S, Tysk C. Systematic review: microscopic colitis. Aliment Pharmacol Ther 2006; 23:1525–1534. Chande N, McDonald JW, Macdonald JK. Interventions for treating lymphocytic colitis. Cochrane Database Syst Rev 2008;(2):CD006096.

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3181 3182 3183 3184 3185 3186 3187 3188 3189 3190 3191 3192 3193 3194 3195 3196 3197 3198 3199 3200 3201 3202 3203 3204 3205 3206 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 3228 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 3239 3240

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29. Chande N, McDonald JW, Macdonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev 2008;(2):CD003575. 30. Stewart MJ, Seow CH, Storr MA. Prednisolone and budesonide for short- and long-term treatment of microscopic colitis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2011;9:881–890. 31. Rutgeerts P. 1994.

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Reprint requests Address requests for reprints to: Chair, Clinical Guidelines Committee, AGA National Ofﬁce, 4930 Del Ray Avenue, Bethesda, Maryland 20814. e-mail: Q1 [email protected]; telephone: (301) 941-2618. Conﬂicts of interest All members were required to complete disclosure statements. These statements are maintained at the American Gastroenterological Association Institute headquarters in Bethesda, Maryland, and none of the disclosures Q2 were potentially related to the content of this guideline.

AGA SECTION

3241 3242 3243 3244 3245 3246 3247Q21 3248 3249 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270 3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 3298 3299 3300

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3301 3302 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 3356 3357 3358 3359 3360

-

3361 3362 3363 3364 3365 3366 3367 3368 3369 3370 3371 3372 3373 3374 3375 3376 3377 3378 3379 3380 3381 3382 3383 3384 3385 3386 3387 3388 3389 3390 3391 3392 3393 3394 3395 3396 3397 3398 3399 3400 3401 3402 3403 3404 3405 3406 3407 3408 3409 3410 3411 3412 3413 3414 3415 3416 3417 3418 3419 3420

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Appendix 1. Literature Search Strategy: Prevalence and Biopsy Characteristics of Patients With MC

#

Searches

1 2 3

exp Colitis, Microscopic/ use mesz,cctr,coch,clhta exp microscopic colitis/ use emez ((microscopic or collagenous or lymphocytic) adj2 colitis).ti,ab. or/1-3 exp Colitis, Microscopic/di [Diagnosis] exp Colonoscopy/ (colonoscop* or (colon adj endoscop*)).ti,ab. exp Biopsy/ use mesz,cctr,coch,clhta exp intestine biopsy/ use emez (biopsy or biopsied or biopsies).ti,ab. or/5-10 4 and 11 limit 12 to (editorial or letter or note or case reports or comment) [Limit not valid in CCTR,CDSR,CLHTA,Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) In-Process; records were retained] Case Report/ 12 not (13 or 14) remove duplicates from 15

4 5 6 7 8 9 10 11 12 13

14 15 16

Results 436 588 3015 3161 298 67846 52968 229496 18651 674022 874623 1881 359

3579331 1239 837

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28.e1

3421 3422 3423 3424 3425 3426 3427 3428 3429 3430 3431 3432 3433 3434 3435 3436 3437 3438 3439 3440 3441 3442 3443 3444 3445 3446 3447 3448 3449 3450 3451 3452 3453 3454 3455 3456 3457 3458 3459 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 3474 3475 3476 3477 3478 3479 3480

28.e2

3481 3482 3483 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 3495 3496 3497 3498 3499 3500 3501 3502 3503 3504 3505 3506 3507 3508 3509 3510 3511 3512 3513 3514 3515 3516 3517 3518 3519 3520 3521 3522 3523 3524 3525 3526 3527 3528 3529 3530 3531 3532 3533 3534 3535 3536 3537 3538 3539 3540

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Appendix 2. Literature Search Strategy – Induction and Maintenance of Remission of MC Search date: August 3, 2014 EBM Reviews - Cochrane Central Register of Controlled Trials June 2014, EBM Reviews - Cochrane Database of

Searches

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

exp Colitis, Microscopic/ use mesz,cctr,coch,clhta exp microscopic colitis/ use emez ((collagenous or microscopic or lymphocytic) adj2 colitis).ti,ab. or/1-3 exp Bismuth/ use mesz,cctr,coch,clhta exp Salicylates/ use mesz,cctr,coch,clhta exp bismuth salicylate/ use emez bismuth.ti,ab. exp Budesonide/ (pulmicort or horacort or rhinocort or budesonide).ti,ab. exp Cholestyramine Resin/ use mesz,cctr,coch,clhta exp colestyramine/ use emez (Cholestyramin* or colestyramin* or Questran or Cholybar or Olestyr).ti,ab. exp Sulfasalazine/ use mesz,cctr,coch,clhta exp salazosulfapyridine/ use emez (Sulfasalazine or salazosulfapyridine or Azulﬁdine or Salazopyrin or Sulazine).ti,ab. exp Mesalamine/ use mesz,cctr,coch,clhta exp mesalazine/ use emez (Mesalazine or mesalamine or 5-aminosalicylic acid or 5-ASA or Asacol or Pentasa or Salofalk or Mezavant or Canasa or Rowasa or Delzicol or Lialda or Apriso).ti,ab. exp Prednisone/ (Cortan or Deltasone or Orasone or Prednisone or Sterapred).ti,ab. exp Azathioprine/ (Azasan or Azathioprine or Imuran or Thiopurine*).ti,ab. exp Metronidazole/ (Flagyl or Metronidazole).ti,ab. exp Methotrexate/ (methotrexate or MTX or Rheumatrex or Trexall or Amethopterin).ti,ab. exp Antibodies, Monoclonal/ use mesz,cctr,coch,clhta (Inﬂiximab or Remicade).ti,ab. exp Inﬂiximab/ use emez exp Adalimumab/ use emez (Humira or Adalimumab).ti,ab. exp Ileostomy/ ileostom*.ti,ab. exp Colectomy/ use mesz,cctr,coch,clhta exp Anastomosis, Surgical/ use mesz,cctr,coch,clhta exp proctocolectomy/ use emez exp anastomosis/ use emez (anastomosis or Proctocolectomy).ti,ab. or/5-39 4 and 40 limit 41 to (editorial or letter or note or case reports or comment) [Limit not valid in CCTR,CDSR,CLHTA,Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) In-Process; records were retained] Case Report/ 41 not (42 or 43) remove duplicates from 44

43 44 45

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Systematic Reviews 2005 to June 2014, EBM Reviews Health Technology Assessment 2nd Quarter 2014, Embase 1980 to 2014 Week 31, Ovid MEDLINE(R) 1946 to July Week 4 2014, Ovid MEDLINE(R) In-Process & Other NonIndexed Citations August 01, 2014

#

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

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Results 437 589 3015 3161 5262 66277 1744 12662 20193 12016 2793 8760 4960 4007 19164 7031 3076 12461 9266 164408 53584 84699 33945 62112 29405 159974 81072 185494 21308 29701 15571 10327 14297 11256 15635 69526 3850 119978 100208 1031152 985 213 3581344 592 430

3541 3542 3543 3544 3545 3546 3547 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558 3559 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 3570 3571 3572 3573 3574 3575 3576 3577 3578 3579 3580 3581 3582 3583 3584 3585 3586 3587 3588 3589 3590 3591 3592 3593 3594 3595 3596 3597 3598 3599 3600

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Appendix 3. Forest Plots for the Cited Comparisons

web 4C=FPO

3601 3602 3603 3604 3605 3606 3607 3608 3609 3610 3611 3612 3613 3614 3615 3616 3617 3618 3619 3620 3621 3622 3623 3624 3625 3626 3627 3628 3629 3630 3631 3632 3633 3634 3635 3636 3637 3638 3639 3640 3641 3642 3643 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 3655 3656 3657 3658 3659 3660

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28.e3

3661 3662 3663 3664 3665 3666 3667 3668 3669 3670 3671 3672 3673 3674 3675 3676 3677 3678 3679 3680 3681 3682 3683 3684 3685 3686 3687 3688 3689 3690 3691 3692 3693 3694 3695 3696 3697 3698 3699 3700 3701 3702 3703 3704 3705 3706 3707 3708 3709 3710 3711 3712 3713 3714 3715 3716 3717 3718 3719 3720

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No.

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3781 3782 3783 3784 3785 3786 3787 3788 3789 3790 3791 3792 3793 3794 3795 3796 3797 3798 3799 3800 3801 3802 3803 3804 3805 3806 3807 3808 3809 3810 3811 3812 3813 3814 3815 3816 3817 3818 3819 3820 3821 3822 3823 3824 3825 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 3836 3837 3838 3839 3840

web 4C=FPO

3721 3722 3723 3724 3725 3726 3727 3728 3729 3730 3731 3732 3733 3734 3735 3736 3737 3738 3739 3740 3741 3742 3743 3744 3745 3746 3747 3748 3749 3750 3751 3752 3753 3754 3755 3756 3757 3758 3759 3760 3761 3762 3763 3764 3765 3766 3767 3768 3769 3770 3771 3772 3773 3774 3775 3776 3777 3778 3779 3780

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28.e5

3901 3902 3903 3904 3905 3906 3907 3908 3909 3910 3911 3912 3913 3914 3915 3916 3917 3918 3919 3920 3921 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 3943 3944 3945 3946 3947 3948 3949 3950 3951 3952 3953 3954 3955 3956 3957 3958 3959 3960

web 4C=FPO

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web 4C=FPO web 4C=FPO web 4C=FPO

3961 3962 3963 3964 3965 3966 3967 3968 3969 3970 3971 3972 3973 3974 3975 3976 3977 3978 3979 3980 3981 3982 3983 3984 3985 3986 3987 3988 3989 3990 3991 3992 3993 3994 3995 3996 3997 3998 3999 4000 4001 4002 4003 4004 4005 4006 4007 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 4018 4019 4020

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4261 4262 4263 4264 4265 4266 4267 4268 4269 4270 4271 4272 4273 4274 4275 4276 4277 4278 4279 4280 4281 4282 4283 4284 4285 4286 4287 4288 4289 4290 4291 4292 4293 4294 4295 4296 4297 4298 4299 4300 4301 4302 4303 4304 4305 4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 4316 4317 4318 4319 4320

web 4C=FPO web 4C=FPO

4201 4202 4203 4204 4205 4206 4207 4208 4209 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 4231 4232 4233 4234 4235 4236 4237 4238 4239 4240 4241 4242 4243 4244 4245 4246 4247 4248 4249 4250 4251 4252 4253 4254 4255 4256 4257 4258 4259 4260

Pardi et al

web 4C=FPO

28.e8

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

AGA Section

28.e9

4381 4382 4383 4384 4385 4386 4387 4388 4389 4390 4391 4392 4393 4394 4395 4396 4397 4398 4399 4400 4401 4402 4403 4404 4405 4406 4407 4408 4409 4410 4411 4412 4413 4414 4415 4416 4417 4418 4419 4420 4421 4422 4423 4424 4425 4426 4427 4428 4429 4430 4431 4432 4433 4434 4435 4436 4437 4438 4439 4440

web 4C=FPO

4321 4322 4323 4324 4325 4326 4327 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 4338 4339 4340 4341 4342 4343 4344 4345 4346 4347 4348 4349 4350 4351 4352 4353 4354 4355 4356 4357 4358 4359 4360 4361 4362 4363 4364 4365 4366 4367 4368 4369 4370 4371 4372 4373 4374 4375 4376 4377 4378 4379 4380

2015

web 4C=FPO

-

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

Gastroenterology Vol.

-,

No.

-

4501 4502 4503 4504 4505 4506 4507 4508 4509 4510 4511 4512 4513 4514 4515 4516 4517 4518 4519 4520 4521 4522 4523 4524 4525 4526 4527 4528 4529 4530 4531 4532 4533 4534 4535 4536 4537 4538 4539 4540 4541 4542 4543 4544 4545 4546 4547 4548 4549 4550 4551 4552 4553 4554 4555 4556 4557 4558 4559 4560

web 4C=FPO

4441 4442 4443 4444 4445 4446 4447 4448 4449 4450 4451 4452 4453 4454 4455 4456 4457 4458 4459 4460 4461 4462 4463 4464 4465 4466 4467 4468 4469 4470 4471 4472 4473 4474 4475 4476 4477 4478 4479 4480 4481 4482 4483 4484 4485 4486 4487 4488 4489 4490 4491 4492 4493 4494 4495 4496 4497 4498 4499 4500

Pardi et al

web 4C=FPO

28.e10

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

AGA Section

28.e11

4621 4622 4623 4624 4625 4626 4627 4628 4629 4630 4631 4632 4633 4634 4635 4636 4637 4638 4639 4640 4641 4642 4643 4644 4645 4646 4647 4648 4649 4650 4651 4652 4653 4654 4655 4656 4657 4658 4659 4660 4661 4662 4663 4664 4665 4666 4667 4668 4669 4670 4671 4672 4673 4674 4675 4676 4677 4678 4679 4680

web 4C=FPO web 4C=FPO

4561 4562 4563 4564 4565 4566 4567 4568 4569 4570 4571 4572 4573 4574 4575 4576 4577 4578 4579 4580 4581 4582 4583 4584 4585 4586 4587 4588 4589 4590 4591 4592 4593 4594 4595 4596 4597 4598 4599 4600 4601 4602 4603 4604 4605 4606 4607 4608 4609 4610 4611 4612 4613 4614 4615 4616 4617 4618 4619 4620

2015

web 4C=FPO

-

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

4681 4682 4683 4684 4685 4686 4687 4688 4689 4690 4691 4692 4693 4694 4695 4696 4697 4698 4699 4700 4701 4702 4703 4704 4705 4706 4707 4708 4709 4710 4711 4712 4713 4714 4715 4716 4717 4718 4719 4720 4721 4722 4723 4724 4725 4726 4727 4728 4729 4730 4731 4732 4733 4734 4735 4736 4737 4738 4739 4740

Pardi et al

Gastroenterology Vol.

-,

No.

-

4741 4742 4743 4744 4745 4746 4747 4748 4749 4750 4751 4752 4753 4754 4755 4756 4757 4758 4759 4760 4761 4762 4763 4764 4765 4766 4767 4768 4769 4770 4771 4772 4773 4774 4775 4776 4777 4778 4779 4780 4781 4782 4783 4784 4785 4786 4787 4788 4789 4790 4791 4792 4793 4794 4795 4796 4797 4798 4799 4800

web 4C=FPO

28.e12

PGL 5.4.0 DTD YGAST60132_proof 18 November 2015 7:37 pm ce

American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis

American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis

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