supplementary material

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SUPPLEMENTARY MATERIAL I. Supplementary Appendices

Supplementary Appendix 1: Search strategy EMBASE (Ovid, 1984)

1. random$.tw.

2. factorial$.tw.

3. (crossover$ or cross over$ or crossover$).tw.

4. placebo$.tw.

5. single blind.mp.

6. double blind.mp.

7. triple blind.mp.

8. (singl$ adj blind$).tw.

9. (double$ adj blind$).tw.

10. (tripl$ adj blind$).tw.

11. assign$.tw.

12. allocat$.tw.

13. crossover procedure/

14. double blind procedure/

15. single blind procedure/

16. triple blind procedure/

17. randomized controlled trial/

18. or/1-17 19. Colitis.mp.

20. Inflammatory bowel disease.ti.

21.IBD.ti.

22.Or/19-22

MEDLINE (Ovid, 1946) 1. random$.tw.

2. factorial$.tw.

3. (crossover$ or cross over$ or crossover$).tw.

4. placebo$.tw.

5. single blind.mp.

6. double blind.mp.

7. triple blind.mp.

8. (singl$ adj blind$).tw.

9. (double$ adj blind$).tw.

10. (tripl$ adj blind$).tw.

11. assign$.tw.

12. allocat$.tw.

13. crossover procedure/

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Supplementary Material 2 14. double blind procedure/

15. single blind procedure/

16. triple blind procedure/

17. randomized controlled trial/

18. or/1-17 19. Colitis.mp.

20. Inflammatory bowel disease.ti.

21.IBD.ti.

22.Or/19-22

Cochrane Library (CENTRAL, 2017 Issue 7)

#1 Colitis

#2 IBD

#3 Inflammatory bowel disease

#4 #1 or #2 or #3

(3)

Supplementary Material 3 Supplementary Appendix 2: Outcome assessment bias and intention to treat analysis

For induction studies, outcome assessment was unclear in 23 (34%) and low in 45 (66%) studies.

No studies rated high. For histologic outcomes, analysis was by ITT in 34 (50%) or not in 31 (46%) studies and unclear in 3 (4%) studies. For endoscopic outcomes, analysis was by ITT in 37 (54%) or not in 25 (37%) studies and unclear in 6 (9%) studies. For maintenance studies, outcome assessment was unclear in 4 (57%) and low in 3 (43%) studies. No studies rated high.

For histologic outcomes, analysis was by ITT in 6 (86%) studies and not in 1 (14%) study. The endoscopic outcomes were also conducted by ITT in 6 (86%) studies and not in 1 (14%) study.

(4)

Supplementary Material 4 Supplementary Appendix 3: Additional extracted variables

1) General information (title, journal, year, publication type);

2) Study information (design, methods of randomization, concealment of allocation and blinding, location, a priori and post hoc analyses);

3) Intervention and control (type and dose of medication; placebo or active comparator);

4) Eligibility (total number of patients screened and randomized);

5) Baseline characteristics for each arm (age, sex, disease severity, disease extent, concurrent medications, prior medications, mean entry histologic and endoscopic scores, smoking status, CRP, fecal calprotectin);

6) Baseline inclusion requirements of active endoscopy or histology

7) Follow-up (length of follow up, withdrawals, number of patients lost to follow-up);

8) Histologic and endoscopic indices used;

9) Definitions of histologic and endoscopic outcomes;

10) Primary and secondary outcomes; and

11) Risk of bias domains (including blinding of histologic outcome assessment).

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Supplementary Material 5 Supplementary Appendix 4:

References are provided for articles excluded from quantitative synthesis due to only containing continuous outcomes, without providing histologic remission or response rates. These are categorized by drug class. Reasons for exclusion of these articles included histology being presented as continuous variable, uninterpretable histologic data, multiple biopsy scores in different locations without reporting histologic response rates, only providing descriptive data, evaluation of at less than 4 weeks or unknown patient sample sizes included in each group.

a) Oral ASA medications: (115-133).

b) Topical ASA medications: (134-140) c) ASA suppositories: (141, 142)

d) Rectal topical steroids: (76, 77, 143-151) e) Oral topical steroids: (152)

f) Budesonide MMX: (153) g) Placebo (96-98, 106, 154-162)

h) Other medications: enoxaparin (162),oral disodium cromoglycate (154), EGFR

enema(157), Fecal Microbiota Transplantation (155), pegylated interferon alpha (158), topical short chain fatty acid or butyrate therapy (156, 159, 160) or oral sodium

butyrate(161).

(6)

Supplementary Material 6 Supplementary Appendix 5: Data categorization based on drug class, dosing and route of administration:

For topical aminosalicylate (ASA) enemas or foams (which included both 4-ASA and 5ASA formulations), data was pooled for doses of 1g per day or more (113). For 5-ASA suppositories, data was pooled for doses of 1g per day or more(113). For oral aminosalicylate (including 4- ASA, balsalzide, sulphasalazine, olsalazine and various mesalazine formulations), data was pooled for standard and high doses combined, and low dose separately. (113). Standard dose were: 2g/d or more for Olsalaine and Mezalazine, 6g/d for Balsalazide, and 4g/d for

Sulfasalazine. (113, 114). Data was pooled for rectally administered topical steroids (prednisolone, budesonide, hydrocortisone, beclomethasone dipropionate) of various

formulations and doses. Oral topical steroids of various doses and formulations (budesonide, fluticasone propionate and beclomethasone dipropionate) and oral systemic steroids were also analyzed separately. Budesonide MMX was analyzed separately.

(7)

Supplementary Material 7 Supplementary Appendix 6: Outcomes rates of drug classes with too few studies for meta- analysis

A) Oral systemic corticosteroids:

The reported induction rates for histological response were 39% (41/105) ⁷⁶ and 61% (22/36) ⁷⁴, histological remission was 17% (6/36)⁷⁴, endoscopic response was 69% (25/36)⁷⁴ and

endoscopic remission was 63% (62/99)⁷⁶ and 17% (6/36)⁷⁴

B) Budesonide MMX-endoscopic outcomes: Endoscopic response (34%, 74/218⁷⁷ and 39%, 94/24⁴⁴) and remission (20%, 46/230⁸¹) rates were reported.

C) Immunosuppressives (azathioprine):

Only histological 42% (5/12) and endoscopic remission 42% (5/12)⁵² rates were reported, at 78 weeks.

D) Ozanimod:

Induction histological and endoscopic remission rates were 18% (24/132) and 31% (41/132), respectively. Maintenance histological and endoscopic remission rates were 27% (36/132) and 33% (43/132), respectively.

E) Placebo-maintenance outcomes:

The histological remission rates were 45% (14/31)48 and 7.7% (5/65) and the endoscopic remission rates were 45% (14/31)48 and 12% (8/65).^14-16,49

(8)

Supplementary Material 8 Supplementary Appendix 7: Outcomes data from omitted trials of approved biologic

therapies for UC

1) Tumor necrosis factor (TNF) antagonists approved for UC A) Golimumab⁸⁹,

Among 89 patients in the substudy of the PURSUIT SC trial, histologic healing was defined as the presence of factors associated with endoscopic healing (absence of histological evidence of ulceration & erosion, no evidence of crypt destruction, with <5% neutrophil infiltration of the epithelia). Week 6 histologic healing rates were stratified by Mayo Clinic endoscopy scores (MCES). These rates were 100% (14/14), 68.1% (47/69), 19.9% (31/56), and 16.3%(17/104), for patients with a MCES of 1, 2 and 3 respectively.

B) Infliximab⁹⁰,

Of patients from the ACT 1 trial, approximately 35 patients per group (infliximab 5mg/kg, 10mg/kg or placebo) were included in the substudy. Between multiple collection times (weeks 8 and 30), histologic healing (Geboes grade 0) rates were 35% and 24% in the infliximab and placebo groups, respectively. Histologic healing rates at individual time points and the exact number of patients per group werenot presented.

2) Anti-integrin therapies approved for UC⁹¹

In a placebo controlled RCT in UC patients, MLN02, a humanized antibody to the 47 integrin, was administered at 0.5mg/kg or 2mg/kg on day 1 and 29. A greater improvement in mean histologic scores (modified Riley score) was seen in treatment groups than in the placebo group.

Compared to baseline (MLN02 0.5mg/kg: 5.9 +/-1.3, MLN02 2mg/kg: 6.2+/-1.0, placebo: 5.7+/- 1.5), mean histologic scores were lower in treatment groups compared to placebo at week 4 (MLN02 0.5mg/kg: 3.9 +/-2.5, MLN02 2mg/kg: 4.5+/-2.5, placebo: 5.4+/-1.7, overall p value

<0.001) and week 6 (MLN02 0.5mg/kg: 3.6 +/-2.7, MLN02 2mg/kg: 3.7+/-2.9, placebo: 4.8+/- 2.4, overall p value=0.03).

(9)

II. Supplementary Tables

Supplementary Table 1: Distribution of disease location presented by drug class for induction and maintenance studies.

Induction studies

Drug class Extensive colitis Left-sided colitis Proctitis Extensive or Left- sided

Left-sided or proctitis

Location missing

Total patients overall, N (%) 1185/9382 (12.6) 4421/9382 (47.1) 1891/9382 (20.2) 213/9382 (2.3) 899/9382 (9.6) 773/9382 (8.2) Topical ASA

Reporting location, N Total patients, N Mean (SD) Median (IQR) Range

1

1/1565 (<0.1)

13

903/1565 (57.7) 69.5 (65.0) 41 (29, 114) (3, 217)

11

369/1565 (23.6) 33.5 (51.2) 15 (9, 23) (2, 176)

0

0/1565 (0)

1

27/1565 (1.7)

2

265/1565 (16.9)

ASA Suppository Reporting location, N Total patients, N Mean (SD) Median (IQR) Range

0 0/601 (0)

6

596/601 (99.2) 99.3 (150.0) 41 (29.8, 59.8) (19, 403)

0 0/601 (0)

0

5/601 (0.8)

Oral ASA normal or high Reporting location, N Total patients, N Mean (SD) Median (IQR) Range

13

455/2120 (21.5) 35.0 (27.6) 34 (9, 47) (3, 88)

15

1004/2120 (47.4) 66.9 (73.1) 59 (18, 82) (1, 292)

9

396/2120 (18.7) 44.0 (46.5) 21 (10, 87) (8, 134)

0

0/2120 (0)

2

71/2120 (3.3)

6

194/2120 (9.2)

Oral ASA low

6

73/456 (16.0) 12.2 (14.5) 6 (3.5, 13.8) (2, 40)

7

162/456 (35.5) 23.1 (28.9) 14 (7.5, 22.5) (2, 86)

5

209/456 (45.8) 41.8 (39.1) 20 (16, 59) (11, 103)

0 0/456 (0)

5

12/456 (2.6)

Oral topical steroid Reporting location, N Total patients, N Mean (SD) Median (IQR) Range

5

129/772 (16.7) 25.8 (9.4) 26 (21, 32) (13, 37)

6

352/772 (45.6) 58.7 (51.7) 41.5 (18.2, 89.5) (13, 140)

1

14/772 (1.8)

1

100/772 (13.0)

0 0/772 (0)

1

177/772 (22.9)

(10)

Supplementary Material 10

Rectal topical steroid Reporting location, N Total patients, N Mean (SD) Median (IQR) Range

1

2/1551 (0.1)

7

584/1551 (37.7) 83.4 (56.4) 88 (37.5, 120) (14, 167)

10

190/1551 (12.3) 19.0 (22.9) 14.5 (5.5, 19.5) (2, 81)

0

0/1551 (0)

5

767/1551 (49.5) 153.0 (216.0) 64 (40, 100) (26, 537)

3

8/1551 (<0.1)

Budesonide MMX Reporting location, N Total patients, N Mean

Median Range

3

218/764 (28.5) 72.7 (29.1) 60

(52, 106)

3

506/764 (66.2) 169.0 (30.1) 178

(135, 193)

0 0/764 (0)

3

40/764 (5.2)

Systemic steroid Reporting location, N Total patients, N

1

22/143 (15.4)

1

16/143 (11.2)

0 0/143 (0)

1

105/143 (73.4)

0 0/143 (0)

0 0/143 (0) Small molecule

Reporting location, N Total patients, N

1

50/132 (37.9)

1

82/132 (62.1)

0 0/132 (0)

0 0/132 (0) Placebo

9

235/1247 (18.8) 26.1 (12.9) 20 (19, 37) (10, 49)

16

781/1247 (62.6) 48.8 (44.2) 30 (19.8, 70) (13, 179)

8

117/1247 (9.4) 14.6 (11.5) 12.5 (6.5, 22.5) (1, 31)

1

8/1247 (0.6)

2

34/1247 (2.7) 17.0

17.0 (15, 19)

5

72/1247 (5.8)

Other

0 0/31 (0)

1

31/31 (100)

0 0/31 (0)

0 0/31 (0) Maintenance Studies

Total patients overall, N (%) 124/719 (17.3) 262/719 (36.4) 10/719 (1.4) 0/719 (0) 0/719 (0) 323/719 (44.9) Oral ASA normal to high

3

34/167 (20.4) 11.3 (11.0) 5

(5, 24)

3

69/167 (41.3) 23.0 (28.6) 8

(5, 56)

2

8/167 (4.8) 4.0 4.0 (3, 5)

0 0/167 (0)

1

56/167 (33.5)

Oral ASA low

1

12/312 (3.8)

1

64/312 (20.5)

0 0/312 (0)

3

236/312 (75.6) Azathioprine

Reporting location, N 1 1 1 0 0 0

(11)

Total patients, N 4/12 (33.3) 6/12 (50.0) 2/12 (16.7) 0/12 (0) 0/12 (0) 0/12 (0)

Small molecule

1

50/132 (37.9)

1

82/132 (62.1)

0 0/132 (0)

0 0/132 (0) Placebo

1

24/96 (25.0)

1

41/96 (42.7)

0 0/96 (0)

1

31/96 (32.3)

(12)

Supplementary Table 2: Timepoint of histologic and endoscopic outcome assessment presented (in weeks) by drug class

Induction studies

Drug class N Mean (SD),

weeks

Median (IQR), weeks

Range, weeks Histologic response

Topical ASA 13 5.1 (1.6) 4 (4, 6) (4, 8)

ASA suppository 3 4 (0) 4 (4, 4)

Oral ASA normal or high dose 9 6.8 (1.6) 8 (6, 8) (4, 8)

Oral ASA low dose 4 6.3 (2.1) 6.5 (4.8, 8.0) (4, 8)

Oral, local corticosteroid 4 5.0 (2.0) 4 (4, 5) (4, 8)

Topical corticosteroid 13 4.8 (1.5) 4 (4, 4) (4, 8)

Systemic corticosteroid 2 4.0 (0) 4 (4, 4)

Placebo 14 5.8 (2.8) 5 (4, 8) (1, 12)

Other 1 4

Histologic remission

Topical ASA 13 5.5 (1.9) 4 (4, 8) (4, 8)

ASA suppository 6 4.3 (0.8) 4 (4, 4) (4, 6)

Oral ASA low dose 3 8.0 (4.0) 8 (4, 12)

Topical corticosteroid 8 5.3 (1.8) 4 (4, 6.5) (4, 8)

Budesonide MMX 3 8 (0) 8 (8, 8)

Systemic corticosteroid 1 4

Small molecule 1 8

Placebo 18 6.8 (3.1) 8 (4, 8) (1, 12)

Endoscopic response

Topical ASA 11 4.7 (1.4) 4 (4, 5) (4, 8)

ASA suppository 3 4 (0) 4 (4, 4)

Oral ASA low dose 4 6.3 (2.1) 6.5 (4.8, 8) (4, 8)

Budesonide MMX 2 8 8 (8, 8)

Systemic corticosteroid 1 4

Placebo 12 5.8 (1.8) 5.5 (4, 8) (4, 8)

Endoscopic remission

Topical ASA 16 5.3 (1.8) 4 (4, 6.5) (4, 8)

ASA suppository 6 4.3 (0.8) 4 (4, 4) (4, 6)

Oral ASA low dose 2 10 10 (9, 11)

Budesonide MMX 1 8

(13)

Systemic corticosteroid 2 4 4 (4, 4)

Small molecule 1 8

Placebo 14 7.2 (3.0) 8 (4, 8) (4, 12)

Other 1 4

Maintenance studies Histologic remission

Oral ASA normal or high dose 4 52.0 (21.2) 52 (45.5, 58.5) (26, 78)

Oral ASA low dose 4 39.0 (15.0) 39 (26, 52) (26, 52)

Immunosuppressive 1 78

Small molecule 1 32

Placebo 2 29 29 (26, 32)

Endoscopic remission

Oral ASA normal or high dose 4 52.0 (21.2) 52 (45.5, 58.5) (26, 78)

Oral ASA low dose 4 39.0 (15.0) 39 (26, 52) (26, 52)

Immunosuppressive 1 78

Small molecule 1 32

Placebo 2 29 29 (26, 32)

(14)

Supplementary Material 14 Supplementary Table 3: Mean histology score at study entry presented by scoring index

Drug class Histology score

Induction studies Maintenance studies Non-standard definitions

Using Definition, N Reporting mean/median, N Mean (SD)

Median, IQR Range

15 10 6.4 (6.3) 3.0 (2.1, 10.6) (2.0, 17.2)

N/A

Floren

Using Definition, N Reporting mean/median, N Mean

10 1 4.1

N/A

Truelove and Richards Using Definition, N Reporting mean/median, N Mean (SD)

Median, IQR Range

11 9 2.0 (0.2) 2.0 (1.9, 2.0) (1.7, 2.3)

4 1 0 Riley

Median, IQR Range

10 2

2.7 (0.05) 2.7 (2.7, 2.8) (2.7, 2.8)

N/A

Ruddell

Using Definition, N Reporting mean/median, N

1 0

N/A Wright and Truelove

Using Definition, N Reporting mean/median, N Median

1 1 2.5

N/A

Willoughby Using Definition, N Reporting mean/median, N

1 0

N/A Fredd

1 0

N/A Powell Tuck

2 0

N/A Saverymuttu

Median, IQR Range

4 2 4.6 (1.0) 4.6 (4.3, 4.9) (3.9, 5.3)

N/A

Geboes

(15)

Supplementary Material 15 Using Definition, N

Reporting mean/median, N Mean (SD)

Median, IQR Range

12 7 3.1 (0.6) 3.1 (2.8, 3.3) 2.6, 3.5)

1 0 N/A

Criteria not stated Using definition, N

Reporting mean/median, N

5 0

2 0

(16)

Supplementary Material 16 Supplementary Table 4: Mean endoscopy score at trial entry presented by scoring index

Drug class Endoscopy score

Induction studies Maintenance studies Non-standard definitions: Using Definition,

N

Median, IQR Range

18 12 5.4 (3.4) 5.1 (2.2, 8.3) (2.0, 10.3)

N/A

Baron: Using Definition, N Reporting mean/median, N Mean (SD)

Median, IQR Range

13 8 2.1 (0.5) 2.1 (2.0, 2.4) (0.9, 2.8)

4 0 N/A

Truelove and Richards: Using Definition, N Reporting mean/median, N

Not reporting mean/median, N

2 0 2

N/A

Rachmilewitz: Using Definition, N Reporting mean/median, N

Mean (SD) Median, IQR Range

11 10 7.3 (0.6) 7.3 (6.7, 7.6) (6.6, 8.4)

N/A

UCDAI endoscopy subscore: Using Definition, N

3 0

N/A

St. Mark endoscopy subscore: Using Definition, N

1 0

N/A

Riley endoscopy index: Using Definition, N Reporting mean/median, N

Median, IQR

1 1 7.4

N/A

Mayo endoscopic subscore: Using Definition, N

Median, IQR Range

8 5 3.2 (1.6) 2.5 (2.5, 2.6) (2.2, 6.1)

1 1 2.5

Dick endoscopic score: Using Definition, N Reporting mean/median, N

1 0

N/A Lofberg score: Using Definition, N

1 0

N/A Danielsson: score: Using Definition, N

1 0

N/A Endoscopic index: Using definition, N

Reporting mean/median, N Median, IQR

2 1 6.2

N/A

Sutherland disease activity index: Using definition, N

1 1

N/A

(17)

Supplementary Material 17 Reporting mean/median, N

Median, IQR

2.0 Endoscopic grading system: Using definition, N

Reporting mean/median, N Median, IQR

1 1 9.5

N/A

Criteria not stated: Using criteria, N Reporting mean/median, N

Median, IQR

3 1 2.0

2 0 N/A

(18)

Supplementary Material 18 Supplementary Table 5: Risk of bias assessment

Study Random

Sequence Generation

Allocation Concealment

Blinding of Participants and Personnel

Blinding of outcome assessment

Incomplete Outcome Data

Selective Outcome Reporting

Other Sources of Bias

Andus 2010

Unclear Risk

High Risk

Unclear Risk

High Risk

Low Risk

Low Risk Angus

1992

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Atreya

2016

Low Risk

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Azad Khan

1980

Unclear Risk

High Risk

Low Risk

Low Risk Bar Meir

2003

Unclear Risk

High Risk

Low Risk

Low Risk Bianchi

Porro 1994

Low Risk

High Risk

Low Risk

Low Risk Campieri

1990B*

Low Risk

Unclear Risk

Low Risk

Low Risk Campieri

1988

Unclear Risk

High Risk

Low Risk

Low Risk Campieri

2003

Low Risk

High Risk

Low Risk

High Risk

Low Risk Campieri

1991

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Campieri

1990A*

Low Risk

Unclear Risk

Low Risk

Low Risk Celasco

2010

Low Risk

Unclear Risk

High Risk

Low Risk Danielsson

1987

Low Risk

High Risk

Low Risk

Low Risk De Bievre

2007

Unclear Risk

Low Risk

Unclear Risk

High Risk

Low Risk Di Biasi

1999

Low Risk

Unclear Risk

Low Risk

Low Risk Dissanayake

1973

Unclear Risk

Low Risk

(19)

Eliakim 2007

Low Risk

High Risk

Low Risk

Low Risk Fleig

1988

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Forbes

2005

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Gibson

2006

Low Risk High Risk

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Ginsberg

1988

Unclear Risk

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Gionchetti

1997

Low Risk

High Risk

Low Risk

Low Risk Gionchetti

1998

Low Risk

High Risk

Low Risk

Low Risk Gionchetti

1999

Low Risk

High Risk

Low Risk

Low Risk Green

2002

High Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Gross

2006

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Unclear Risk

Low Risk Gross

2009

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Gross

2011

Low Risk

Unclear Risk

Low Risk

Low Risk Halpern

1991

Unclear Risk

Low Risk

High Risk

Low Risk

Low Risk Hanauer

1998

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Hartmann

2010

Low Risk

High Risk

Unclear Risk

Low Risk

Low Risk Hawthhorne

1993

Unclear Risk

High Risk

Low Risk Hetzel

1988

Low Risk

Low Risk Karner

2014

Low Risk

Unclear Risk

Low Risk

(20)

Knittel 2013

Unclear Risk

Low Risk

Unclear Risk

High Risk

Low Risk Kruis

2009

Low Risk

Low Risk Kruis

2003

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Lee

1996

Low Risk

Hig h Risk

High Risk

Low Risk

Low Risk Lemann

1995

Unclear Risk

High Risk High Risk

Low Risk

Low Risk Liang

2008

High Risk

Low Risk

High Risk

Low Risk Lofberg

1996

Low Risk

Low Risk Lofberg

1994

Low Risk

High Risk

Low Risk

Low Risk Lopes Pontes

1988

Unclear Risk

Low Risk Malchow

2002

Low Risk

High Risk

Low Risk

Low Risk Mansfield

2002

Unclear Risk

Low Risk

High Risk

Low Risk

Low Risk Marakhouski

2005

Unclear Risk

Low Risk

Unclear Risk

Low Risk

Low Risk Mayer

2013

Low Risk

Unclear Risk Mulder

1988

Unclear Risk

Low Risk

Low Risk Mulder

1989

Unclear Risk

Low Risk

Low Risk Mulder

1996

Low Risk

High Risk

Low Risk O'Donnell

1992

Unclear Risk

Low Risk

High Risk

Low Risk Paoluzzi

2002

Unclear Risk

High Risk

Unclear Risk

Low Risk

(21)

Paoluzzi 2005

Unclear Risk

High Risk

Unclear Risk

Low Risk

Low Risk Potrotnieks

2000

Low Risk

High Risk

Low Risk Prantera

2005

Low Risk

Unclear Risk

Low Risk

Low Risk Pruitt

2002

Unclear Risk

Low Risk

Low Risk Pullan

1993

Unclear Risk

Low Risk

Low Risk Rao

1989

Unclear Risk

Low Risk

Low Risk Rizzello

2001

Unclear Risk

Low Risk

Low Risk Rubin

2017

Low Risk

Low Risk Sandborn

1994

Low Risk

Low Risk Sandborn

2012

Low Risk

High Risk

Low Risk Sandborn

2016D*

Low Risk

Low Risk Sandborn

2016G*

Low Risk

Unclear Risk

Low Risk

Low Risk Sandborn

2016A*

Low Risk

Low Risk Sharma

1992

Unclear Risk

Low Risk

High Risk

Low Risk Sood

2002

Low Risk

Unclear Risk

Low Risk

High Risk

Low Risk Sood

2003

Unclear Risk

High Risk

Unclear Risk

Low Risk

Unclear Risk Steinhart

1996

Unclear Risk

Low Risk

Low Risk Travis

2005

Unclear Risk

Low Risk

Travis Low Low Low Low Low High Low

(22)

2014 Risk Risk Risk Risk Risk Risk Risk

Van der Heide 1988

Unclear Risk

Low Risk

Low Risk Wang

2016

Unclear Risk

High Risk

Low Risk

Low Risk Willoughby

1988

Low Risk

*Campieri 1990A studies Mesalazine suppositories 1.5g vs. 1g daily vs placebo, Campieri 1990B analyses Mesalazine 0.5g three times daily vs placebo, Sandborn 2016A analyzes Ozanimod therapy, Sandborn 2016D analyzes Anti MMP9 therapy, Sandborn 2016G analyzes Eldelumab therapy.

(23)

Supplementary Material 23 Supplementary Table 6: Univariable analysis for factors influencing placebo histologic

outcomes Placebo

Factor OR (95% CI) P-value Heterogeneity

I² (%) Publication year (per 5-year increment) 1.24 (1.01, 1.52) 0.035 61 Blinded histopathology reading (Yes vs No/Unclear) 1.12 (0.46, 2.71) 0.80 69 Documentation of active endoscopy at baseline (Yes vs No) 1.21 (0.53, 2.73) 0.65 67 Required documentation of histologic activity at baseline

(Yes vs No)

0.61 (0.28, 1.31) 0.20 59 Proportion of patients using corticosteroids at baseline (per

10% increase)

1.03 (0.88, 1.19) 0.73 70 Proportion of patients with extensive disease (per 10%

increase)

1.05 (0.84, 1.31) 0.65 69 Proportion of patients with mild disease (per 10% decrease) 1.02 (0.87, 1.19) 0.82 67 Proportion of patients with severe disease (per 10% increase) 0.76 (0.52, 1.12) 0.17 62 Active therapy

Factor OR (95% CI) P-value Heterogeneity

I² (%) Publication year (per 5-year increment) 1.01 (0.88, 1.15) 0.92 92 Blinded histopathology reading (Yes vs No/Unclear) 0.62 (0.39, 0.97) 0.038 91 Documentation of active endoscopy at baseline (Yes vs No) 1.56 (0.99, 2.46) 0.056 91 Required documentation of histologic activity at baseline

(Yes vs No)

0.52 (0.34, 0.80) 0.0028 90 Proportion of patients using corticosteroids at baseline (per

10% increase)

0.98 (0.95, 1.14) 0.89 91 Proportion of patients with extensive disease (per 10%

increase)

0.85 (0.75, 0.97) 0.013 90 Proportion of patients with mild disease (per 10% decrease) 0.84 (0.76, 0.93) 0.0014 90 Proportion of patients with severe disease (per 10% increase) 1.08 (0.55, 2.11) 0.83 93

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Supplementary Material 24 III. Supplementary Figures

Supplementary Figure 1: Forest plot of pooled histologic response (A) and remission (B) rates for induction trials of oral aminosalicylates and histologic remission rates for maintenance trials (C), each stratified by criterion definitions. Overall heterogeneity statistics for induction

histologic response (I²=94%, Q(14)=125.7, p<0.0001) and histologic remission (I²=84%, Q(12)=66.7, p<0.0001) and maintenance remission (I²=93%, Q(5)=98.7, p<0.0001)..

1A

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Supplementary Material 25 1B

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Supplementary Material 26 1C

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Supplementary Material 27 Supplementary Figure 2: Forest plot of pooled endoscopic response (A) and remission (B) rates for induction trials of oral aminosalicylates and endoscopic remission rates for maintenance trials (C), each stratified by criterion definitions. Overall heterogeneity statistics induction endoscopic response (I²=92%, Q(12)=159.0, p<0.0001) and endoscopic remission (I²=90%, Q(12)=118.7, p<0.0001) and maintenance endoscopic remission (I²=93%, Q(5)=104.8, p<0.0001).

2A

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Supplementary Material 30 Supplementary Figure 3: Forest plot of pooled histologic response (A) and remission (B) rates and endoscopic response (C) and remission (D) rates for induction trials of topical

aminosalicylates, each stratified by criterion definitions. Overall heterogeneity statistics

histologic response (I²=83%, Q(12)=42.8, p<0.0001), histologic remission (I²=88%, Q(12)=57.0, p<0.0001), endoscopic response (I²=50%, Q(10)=13.6, p=0.19) and endoscopic remission

(I²=94%, Q(15)=123.8, p<0.0001).

3A

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Supplementary Material 33 3D

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Supplementary Material 34 Supplementary Figure 4: Forest plot of pooled histologic response (A) and remission (B) rates and endoscopic response (C) and remission (D) rates for induction trials of aminosalicylate suppositories, each stratified by criterion definitions. Overall heterogeneity statistics histologic response (I²=0%, Q(2)=2.2, p<0.33), histologic remission (I²=89%, Q(5)=44.9, p<0.0001), endoscopic response (I²=0%, Q(2)=1,2, p=0.55) and endoscopic remission (I²=81%, Q(5)=39.2, p<0.0001).

4A

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Supplementary Material 38 Supplementary Figure 5: Forest plot of pooled histologic response (A) and remission (B) rates and endoscopic response (C) and remission (D) rates for induction trials of oral topical

corticosteroids, each stratified by criterion definitions. Overall heterogeneity statistics histologic response (I²=85%, Q (3) =35.4, p<0.0001), histologic remission (I²=92%, Q(6)=52.5, p<0.0001), endoscopic response (I²=83%, Q(3)=29.8, p<0.0001) and endoscopic remission (I²=97%,

Q(4)=25.8, p<0.0001).

5A

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Supplementary Material 42 Supplementary Figure 6. Forest plot of pooled histologic remission rates for induction trials of Budesonide MMX. stratified by criterion definitions. Overall heterogeneity statistics histologic response (I²=93%, Q(2)=37.7, p<0.0001).

6A

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Supplementary Material 43 Supplementary Figure 7: Forest plot of pooled histologic response (A) and remission (B) rates and endoscopic response (C) and remission (D) rates for induction trials of rectal topical

corticosteroids, each stratified by criterion definitions. Overall heterogeneity statistics histologic response (I²=73%, Q(12)=43.7, p<0.0001), histologic remission (I²=80%, Q(7)=36.2, p<0.0001), endoscopic response (I²=82%, Q(11)=47.6, p<0.0001) and endoscopic remission (I²=91%, Q(9)=77.6, p<0.0001).

7A

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Supplementary Material 47 Supplementary Figure 8: Forest plot of pooled histologic response (A) and remission (B) rates and endoscopic response (C) and remission (D) rates for induction trials of placebo, each

stratified by criterion definitions. Overall heterogeneity statistics histologic response (I²=70%, Q(13)=33.8, p=0.001), histologic remission (I²=69%, Q(17)=36.4, p<0.01), endoscopic response (I²=77%, Q(11)=47.0, p<0.0001) and endoscopic remission (I²=72%, Q(13)=47.6, p<0.0001).

8A

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