Aminosalicylates for induction of remission or response in Crohn's disease

Wee‐Chian Lim; Yongjun Wang; John K MacDonald; Stephen Hanauer

doi:10.1002/14651858.CD008870.pub2

Aminosalicilatos para la inducción de remisión o respuesta en la enfermedad de Crohn

Appendices

Appendix 1. Search Strategies

MEDLINE on PUBMED was searched using the following search terms:

#1 crohn*

#2 sulphasalazine OR sulfasalazine OR salazosulphapyr* OR salazosulfapyr* OR salicylazosulphapyr* OR salicylazosulfapyr* OR salazopyrin

#3 mesalamine OR mezalamine OR aminosalicylate* OR aminosalicylic acid OR 5‐aminosalicylate* OR 5‐aminosalicylic acid OR 5‐ASA

#4 #2 OR #3

#5 #4 AND #1

#6 singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo* OR single‐blind* OR double‐blind* OR triple‐blind* OR random* OR (controlled clinical)

#7 #5 AND #6

EMBASE database was searched using the following search terms:

#1 random$.tw.

#2 factorial$.tw.

#3 (crossover$ or cross over$ or cross‐over$).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 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

#20 #18 not #19

#21 exp salazosulfapyridine/

#22 (sulphasalazine or sulfasalazine or salazosulphapyr* or salazosulfapyr* or salicylazosulphapyr* or salicylazosulfapyr* or salazopyrin*).tw.

#23 mesalamine.tw. or exp mesalazine/

#24 exp aminosalicylic acid/

#25 aminosalicylate*.tw. or exp aminosalicylic acid derivative/ or exp aminosalicylic acid/

#26 (mesalazine or aminosalicylic acid or 5‐aminosalicylate* or 5‐aminosalicylic acid or 5‐ASA or olsalazine).tw.

#27 or/21‐26

#28 exp Crohn disease/ or crohn*.tw.

#29 #20 and #27 and #28

OVID MEDLINE(R) database was searched using the following search terms:

#1 random$.tw.

#2 factorial$.tw.

#3 (crossover$ or cross over$ or cross‐over$).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 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

#20 #18 not #19

#21 exp salazosulfapyridine/

#22 (sulphasalazine or sulfasalazine or salazosulphapyr* or salazosulfapyr* or salicylazosulphapyr* or salicylazosulfapyr* or salazopyrin*).tw.

#23 mesalamine.tw. or exp mesalazine/

#24 exp aminosalicylic acid/

#25 aminosalicylate*.tw. or exp aminosalicylic acid derivative/ or exp aminosalicylic acid/

#26 (mesalazine or aminosalicylic acid or 5‐aminosalicylate* or 5‐aminosalicylic acid or 5‐ASA or olsalazine).tw.

#27 or/21‐26

#28 exp Crohn disease/ or crohn*.tw.

#29 #20 and #27 and #28

Cochrance Central Library database was searched using the following search terms:

#1 crohn*

#2 sulphasalazine or sulfasalazine or salazosulphapyr* or salazosulfapyr* or salicylazosulphapyr* or

salicylazosulfapyr*

#3 mesalamine or mezalamine or aminosalicylate* or aminosalicylic acid or 5‐aminosalicylate* or 5‐aminosalicylic

acid or 5‐ASA

#4 #2 or #3

#5 #1 and #4

The Cochrane IBD‐FBD Specialized Register was searched using the following terms:

#1 (sulpha or sulfa or sala or salicyl or mesala or aminosal or 5‐aminosal or 5‐ASA or olsal).ti.

#2 Crohn.ti.

#3 1 and 2

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

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Analysis 1.1

Comparison 1 Sulfasalazine versus placebo, Outcome 1 Induction of remission (CDAI <150), therapeutic response (VHI decrease >=25%) or clinical improvement.

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Analysis 1.2

Comparison 1 Sulfasalazine versus placebo, Outcome 2 Induction of remission (CDAI <150) (Random Effects Model).

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Analysis 1.3

Comparison 1 Sulfasalazine versus placebo, Outcome 3 Induction of remission (CDA I<150) (Fixed Effect Model).

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Analysis 1.4

Comparison 1 Sulfasalazine versus placebo, Outcome 4 Adverse events.

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Analysis 1.5

Comparison 1 Sulfasalazine versus placebo, Outcome 5 Serious adverse events.

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Analysis 1.6

Comparison 1 Sulfasalazine versus placebo, Outcome 6 Withdrawal due to adverse events.

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Analysis 2.1

Comparison 2 Sulfasalazine versus corticosteroids, Outcome 1 Induction of remission (CDAI <150).

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Analysis 2.2

Comparison 2 Sulfasalazine versus corticosteroids, Outcome 2 Adverse events.

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Analysis 2.3

Comparison 2 Sulfasalazine versus corticosteroids, Outcome 3 Serious adverse events.

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Analysis 2.4

Comparison 2 Sulfasalazine versus corticosteroids, Outcome 4 Withdrawal adverse events.

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Analysis 3.1

Comparison 3 Sulfasalazine versus sulfasalazine and corticosteroids, Outcome 1 Induction of remission.

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Analysis 3.2

Comparison 3 Sulfasalazine versus sulfasalazine and corticosteroids, Outcome 2 Withdrawal due to adverse events.

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Analysis 4.1

Comparison 4 Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo, Outcome 1 Decrease in CDAI >=50, HBI >=2 or improvement/remission (as defined by Tvede et al).

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Analysis 4.2

Comparison 4 Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo, Outcome 2 Induction of remission (CDAI <=150 + decrease of >=50 or as defined by Tvede et al).

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Analysis 4.3

Comparison 4 Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo, Outcome 3 Adverse events.

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Analysis 4.4

Comparison 4 Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo, Outcome 4 Withdrawal due to adverse events.

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Analysis 5.1

Comparison 5 Controlled‐release mesalamine (4 g/day) versus placebo, Outcome 1 Mean change in CDAI from baseline (random‐effects model).

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Analysis 5.2

Comparison 5 Controlled‐release mesalamine (4 g/day) versus placebo, Outcome 2 Mean change in CDAI from baseline (fixed‐effect model).

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Analysis 5.3

Comparison 5 Controlled‐release mesalamine (4 g/day) versus placebo, Outcome 3 Adverse events.

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Analysis 5.4

Comparison 5 Controlled‐release mesalamine (4 g/day) versus placebo, Outcome 4 Withdrawal due to adverse events.

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Analysis 6.1

Comparison 6 Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo, Outcome 1 Induction of remission or clinical improvement.

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Analysis 6.2

Comparison 6 Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo, Outcome 2 Induction of remission (CDAI < 150 + decrease >=70).

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Analysis 6.3

Comparison 6 Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo, Outcome 3 Adverse events.

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Analysis 6.4

Comparison 6 Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo, Outcome 4 Withdrawal due to adverse events.

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Analysis 7.1

Comparison 7 Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids, Outcome 1 Induction of remission (CDAI < or =150 with or without decrease of at least 60 points).

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Analysis 7.2

Comparison 7 Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids, Outcome 2 Adverse events.

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Analysis 7.3

Comparison 7 Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids, Outcome 3 Serious adverse events.

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Analysis 7.4

Comparison 7 Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids, Outcome 4 Withdrawal due to adverse events.

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Analysis 8.1

Comparison 8 Mesalamine (4 ‐ 4.5 g/day) versus budesonide, Outcome 1 Induction of remission (CDAI < or = 150).

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Analysis 8.2

Comparison 8 Mesalamine (4 ‐ 4.5 g/day) versus budesonide, Outcome 2 Adverse events.

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Analysis 8.3

Comparison 8 Mesalamine (4 ‐ 4.5 g/day) versus budesonide, Outcome 3 Serious adverse events.

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Analysis 8.4

Comparison 8 Mesalamine (4 ‐ 4.5 g/day) versus budesonide, Outcome 4 Withdrawal due to adverse events.

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Analysis 9.1

Comparison 9 Mesalamine versus sulfasalazine (alone or in combination with corticosteroids), Outcome 1 Induction of remission (CDAI < 150) or clinical improvement.

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Analysis 9.2

Comparison 9 Mesalamine versus sulfasalazine (alone or in combination with corticosteroids), Outcome 2 Adverse events.

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Summary of findings for the main comparison. Sulfasalazine compared to placebo for induction of remission or response in Crohn's disease

Sulfasalazine compared to placebo for induction of remission or response in Crohn's disease
Patient or population: patients with induction of remission or response in Crohn's disease Settings: Inpatient/Outpatient Intervention: Sulfasalazine Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Sulfasalazine
Induction of remission (CDAI <150), therapeutic response (VHI decrease >=25%) or clinical improvement Follow‐up: 17‐26 weeks	291 per 1000¹	442 per 1000 (276 to 706)	RR 1.52 (0.95 to 2.43)	289 (3 studies)	⊕⊕⊝⊝ low^2,3
Induction of remission (CDAI <150) (Random Effects Model) Follow‐up: 17‐18 weeks	311 per 1000¹	429 per 1000 (311 to 588)	RR 1.38 (1 to 1.89)	263 (2 studies)	⊕⊕⊕⊝ moderate⁴
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of meta‐analysis, based on included trials. ² Dowgraded one level due to sparse data (106 events). ³ Dowgraded one level due heterogeneity (I² = 41%). ⁴ Downgraded one level due to sparse data (97 events).

Summary of findings for the main comparison. Sulfasalazine compared to placebo for induction of remission or response in Crohn's disease

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Summary of findings 2. Sulfasalazine compared to Corticosteroids for induction of remission or response in Crohn's disease

Sulfasalazine compared to Corticosteroids for induction of remission or response in Crohn's disease
Patient or population: patients with induction of remission or response in Crohn's disease Settings: Inpatient/Outpatient Intervention: Sulfasalazine Comparison: Corticosteroids
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Corticosteroids	Sulfasalazine
Induction of remission (CDAI <150) Follow‐up: 17‐18 weeks	598 per 1000¹	407 per 1000 (305 to 545)	RR 0.68 (0.51 to 0.91)	260 (2 studies)	⊕⊕⊕⊝ moderate²
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of meta‐analysis, based on included trials. ² Downgraded one level due to sparse data (134 events).

Summary of findings 2. Sulfasalazine compared to Corticosteroids for induction of remission or response in Crohn's disease

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Summary of findings 3. Sulfasalazine compared to Sulfasalazine and corticosteroids for induction of remission or response in Crohn's disease

Sulfasalazine compared to Sulfasalazine and corticosteroids for induction of remission or response in Crohn's disease
Patient or population: patients with induction of remission or response in Crohn's disease Settings: Inpatient/Outpatient Intervention: Sulfasalazine Comparison: Sulfasalazine and corticosteroids
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sulfasalazine and corticosteroids	Sulfasalazine
Induction of remission Follow‐up: 18 weeks	786 per 1000¹	503 per 1000 (369 to 676)	RR 0.64 (0.47 to 0.86)	110 (1 study)	⊕⊕⊕⊝ moderate²
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of the included study ² Downgraded one level due to sparse data (71 events)

Summary of findings 3. Sulfasalazine compared to Sulfasalazine and corticosteroids for induction of remission or response in Crohn's disease

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Summary of findings 4. Controlled‐release mesalamine (1 ‐ 2 g/day) compared to Placebo for induction of remission or response in Crohn's disease

Controlled‐release mesalamine (1 ‐ 2 g/day) compared to Placebo for induction of remission or response in Crohn's disease
Patient or population: patients with induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Controlled‐release mesalamine (1 ‐ 2 g/day) Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Controlled‐release mesalamine (1 ‐ 2 g/day)
Decrease in CDAI >=50, HBI >=2 or improvement/remission (as defined by Tvede et al) Follow‐up: 6‐16 weeks	350 per 1000¹	375 per 1000 (280 to 498)	RR 1.07 (0.8 to 1.42)	342 (3 studies)	⊕⊕⊝⊝ low^2,3
Induction of remission (CDAI <=150 + decrease of >=50 or as defined by Tvede et al) Follow‐up: 16 weeks	444 per 1000¹	649 per 1000 (396 to 1000)	RR 1.46 (0.89 to 2.4)	302 (2 studies)	⊕⊕⊝⊝ low^2,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of meta‐analysis, based on included trials. ² Downgraded one level because two studies in the pooled analysis were rated as high risk of bias for incomplete outcome data. ³ Downgraded one level; due to sparse data (127 events). ⁴ Downgraded one level due to sparse data (61 events).

Summary of findings 4. Controlled‐release mesalamine (1 ‐ 2 g/day) compared to Placebo for induction of remission or response in Crohn's disease

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Summary of findings 5. Controlled‐release mesalamine (4 g/day) compared to Placebo for Induction of remission or response in Crohn's disease

Controlled‐release mesalamine (4 g/day) compared to Placebo for Induction of remission or response in Crohn's disease
Patient or population: patients with Induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Controlled‐release mesalamine (4 g/day) Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Controlled‐release mesalamine (4 g/day)
Mean change in baseline CDAI (Random effects model) Follow‐up: 16 weeks		The mean mean change in baseline cdai (random effects model) in the intervention groups was 19.76 lower (46.22 lower to 6.7 higher)		615 (3 studies)	⊕⊕⊝⊝ low^1,2
Mean change in baseline CDAI (Fixed effects model) Follow‐up: 16 weeks		The mean mean change in baseline cdai (fixed effects model) in the intervention groups was 17.54 lower (35 to 0.08 lower)		615 (3 studies)	⊕⊕⊝⊝ low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Downgraded one level due to moderate heterogeneity (I² = 54%). ² Downgraded one level because all three studies in the pooled analysis were rated as high risk of bias for incomplete outcome data.

Summary of findings 5. Controlled‐release mesalamine (4 g/day) compared to Placebo for Induction of remission or response in Crohn's disease

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Summary of findings 6. Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) compared to Placebo for Induction of remission or response in Crohn's disease

Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) compared to Placebo for Induction of remission or response in Crohn's disease
Patient or population: patients with Induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day)
Induction of remission or clinical improvement ‐ Olsalazine (2 g/day) Follow‐up: 16 weeks	489 per 1000¹	176 per 1000 (88 to 347)	RR 0.36 (0.18 to 0.71)	91 (1 study)	⊕⊝⊝⊝ very low^2,3
Induction of remission or clinical improvement ‐ Asacol (3.2 g/day) Follow‐up: 16 weeks	222 per 1000¹	600 per 1000 (236 to 1000)	RR 2.7 (1.06 to 6.88)	38 (1 study)	⊕⊝⊝⊝ very low^2,4
Induction of remission (CDAI < 150 + decrease >=70) ‐ Asacol (3.2 g/day) Follow‐up: 16 weeks	222 per 1000¹	451 per 1000 (167 to 1000)	RR 2.03 (0.75 to 5.45)	38 (1 study)	⊕⊝⊝⊝ very low^2,5
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of the included study. ² Downgraded one level because the study was rated as high risk of bias for incomplete outcome data. ³ Downgraded two levels due to very sparse data (30 events). ⁴ Downgraded two levels due to very sparse data (16 events). ⁵ Downgraded two levels due to very sparse data (13 events).

Summary of findings 6. Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) compared to Placebo for Induction of remission or response in Crohn's disease

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Summary of findings 7. Delayed‐release mesalamine (3 ‐ 4.5 g/day) compared to Corticosteroids for Induction of remission or response in Crohn's disease

Delayed‐release mesalamine (3 ‐ 4.5 g/day) compared to Corticosteroids for Induction of remission or response in Crohn's disease
Patient or population: patients with Induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Delayed‐release mesalamine (3 ‐ 4.5 g/day) Comparison: Corticosteroids
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Corticosteroids	Delayed‐release mesalamine (3 ‐ 4.5 g/day)
Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) Follow‐up: 8‐12 weeks	526 per 1000¹	547 per 1000 (416 to 716)	RR 1.04 (0.79 to 1.36)	178 (3 studies)	⊕⊕⊕⊝ moderate²
Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) ‐ 3 g/day Follow‐up: 12 weeks	429 per 1000³	407 per 1000 (210 to 793)	RR 0.95 (0.49 to 1.85)	50 (1 study)	⊕⊕⊝⊝ low⁴
Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) ‐ 2.4 g/day Follow‐up: 12 weeks	600 per 1000³	600 per 1000 (366 to 984)	RR 1 (0.61 to 1.64)	50 (1 study)	⊕⊕⊕⊝ moderate⁵
Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) ‐ 4 g/day microgranules Follow‐up: 12 weeks	625 per 1000³	788 per 1000 (512 to 1000)	RR 1.26 (0.82 to 1.92)	44 (1 study)	⊕⊕⊕⊝ moderate⁶
Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) ‐ 4.5 g/day Follow‐up: 8 weeks	529 per 1000³	355 per 1000 (159 to 773)	RR 0.67 (0.3 to 1.46)	34 (1 study)	⊕⊕⊝⊝ low⁷
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of meta‐analysis, based on included trials. ² Downgraded one level due to sparse data (98 events). ³ Control group risk comes from control arm of the included study. ⁴ Downgraded two levels due to very sparse data (21 events). ⁵ Downgraded one level due to sparse data (40 events). ⁶ Downgraded one level due to sparse data (41 events). ⁷ Downgraded two levels due to very sparse data (15 events).

Summary of findings 7. Delayed‐release mesalamine (3 ‐ 4.5 g/day) compared to Corticosteroids for Induction of remission or response in Crohn's disease

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Summary of findings 8. Mesalamine (4 ‐ 4.5 g/day) compared to Budesonide for Induction of remission or response in Crohn's disease

Mesalamine (4 ‐ 4.5 g/day) compared to Budesonide for Induction of remission or response in Crohn's disease
Patient or population: patients with Induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Mesalamine (4 ‐ 4.5 g/day) Comparison: Budesonide
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Budesonide	Mesalamine (4 ‐ 4.5 g/day)
Induction of remission (CDAI < or = 150) ‐ Pentasa (4 g/day) Follow‐up: 16 weeks	602 per 1000¹	337 per 1000 (241 to 470)	RR 0.56 (0.4 to 0.78)	182 (1 study)	⊕⊕⊝⊝ low^2,3
Induction of remission (CDAI < or = 150) ‐ Salofalk (4.5 g/day) Follow‐up: 8 weeks	695 per 1000¹	618 per 1000 (528 to 730)	RR 0.89 (0.76 to 1.05)	307 (1 study)	⊕⊕⊕⊝ moderate
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of the included study. ² Downgraded one level because the study was rated as high risk of bias for incomplete outcome data. ³ Downgraded one level due to sparse data (86 events). ⁴ Downgraded one level due to Ssparse data (202 events).

Summary of findings 8. Mesalamine (4 ‐ 4.5 g/day) compared to Budesonide for Induction of remission or response in Crohn's disease

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Summary of findings 9. Mesalamine compared to Sulfasalazine (alone or in combination with corticosteroids) for Induction of remission or response in Crohn's disease

Mesalamine compared to Sulfasalazine (alone or in combination with corticosteroids) for Induction of remission or response in Crohn's disease
Patient or population: patients with Induction of remission or response in Crohn's disease Settings: Outpatient Intervention: Mesalamine Comparison: Sulfasalazine (alone or in combination with corticosteroids)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sulfasalazine (alone or in combination with corticosteroids)	Mesalamine
Induction of remission (CDAI < 150) or clinical improvement ‐ Salofalk (1.5 g/day) Follow‐up: 8 weeks	733 per 1000¹	865 per 1000 (601 to 1000)	RR 1.18 (0.82 to 1.7)	30 (1 study)	⊕⊝⊝⊝ very low^2,3
Induction of remission (CDAI < 150) or clinical improvement ‐ Salofalk (3.0 g/day) Follow‐up: 12 weeks	885 per 1000¹	832 per 1000 (663 to 1000)	RR 0.94 (0.75 to 1.18)	50 (1 study)	⊕⊕⊝⊝ low^2,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Control group risk comes from control arm of the included study. ² Downgraded one level because the study was rated as high risk for blinding. ³ Downgraded two levels due to very sparse data (24 events). ⁴ Downgraded one level due to sparse data (43 events).

Summary of findings 9. Mesalamine compared to Sulfasalazine (alone or in combination with corticosteroids) for Induction of remission or response in Crohn's disease

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Table 1. Characteristics of Excluded Studies

Study ID	Comparators	Endpoint	Study design	Patient Population	Exclusion reasons
Anonymous 1985	SASP 1 g/15 kg /day alone	Clinical response	Uncontrolled	Active CD	1, 5
Anonymous 1990	5‐ASA 1.5 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Medical/Surgical)	2, 6
Anthonisen 1974	SASP (1.5 g for 3 days followed by 3 g/day) versus Placebo	Clinical improvement	Double‐blind placebo controlled cross‐over	Active CD	7
Arber 1995	5‐ASA 1 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Ardizzone 2004	5‐ASA 3 g/day versus Azathioprine	Clinical and surgical relapse	Open label, randomized	CD in remission (Surgical)	2, 5, 6
Beck 1988	5‐ASA versus SASP	Clinical response	Uncontrolled	Active CD	1
Bergman 1976	SASP + CS versus No Treatment	Clinical relapse	Randomized controlled	CD in remission (Surgical)	2, 4, 6
Blichfeldt 1978	SASP versus prednisolone (Metronidazole/ placebo cross‐over)	Clinical improvement	Double‐blind cross‐over	Active CD	4, 5
Bresci 1994	5‐ASA 2.4 g/day versus No Specific Therapy	Clinical relapse	Randomized controlled	CD in remission (Medical)	2, 6
Brignola 1992	5‐ASA 2 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Brignola 1995	5‐ASA 3 g/day versus Placebo	Endoscopic relapse	Double‐blind placebo controlled	CD in remission (Surgical)	2, 6
Caprilli 1994	5‐ASA 2.4 g/day versus No Treatment	Endoscopic relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Caprilli 2003	5‐ASA 2.4 g/day versus 5‐ASA 4 g/day	Clinical and endoscopic relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Cezard 2009	5‐ASA versus Placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission (Paediatric)	2, 6
Cohen 2000	5ASA versus Placebo	Endoscopic recurrence	Randomized, controlled	CD in remission (Surgical)	2, 6
Colombel 1999	5‐ASA versus Antibiotic	Remission	Randomized controlled	Active CD	5
de Franchis R 1997	5‐ASA 3 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Steroid‐induced)	2, 6
Del Corso 1995	5‐ASA 2.4 g/day versus No Treatment	Clinical relapse	Controlled trial	CD in remission (Medical/Surgical)	2, 6
Dirks 1989	SASP + CS versus Surgery	Clinical relapse	Uncontrolled	CD in remission	1,2,4,5,6
Ewe 1976	SASP versus Placebo	Relapse	Double‐blind	CD in remission	2, 6
Ewe 1984	SASP, radical versus restricted surgery	Clinical relapse	Partially randomized, double‐blind	CD in remission (Surgical)	2,6
Ewe 1986	SASP, radicality of surgery	Clinical relapse		CD in remission (Surgical)	2,6
Ewe 1989	SASP versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Fiasse 1990	5‐ASA versus Placebo	Relapse	Double‐blind placebo‐controlled	CD in remission (Surgical)	2, 6
Florent 1996	5‐ASA 3 g/day versus Placebo	Endoscopic relapse	Double‐blind placebo‐controlled	CD in remission (Surgical)	2, 6
Gendre 1993	5‐ASA 2 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Gerhardt 2001	5‐ASA versus Boswellia serrata extract H15	Change in CDAI	Randomized controlled	Active CD	5
Goldstein 1987	SASP alone	Clinical response	Retrospective	Active small bowel CD	1, 5
Griffiths 1993	5‐ASA 50 mg/kg versus Placebo	Change in CDAI, VHI	Randomized controlled	Active small bowel CD (Paediatric)	2
Guslandi 2000	5‐ASA 3 g/day versus 5‐ASA 2 g/day + Saccharomyces boulardii (yeast)	Clinical relapse	Randomized controlled	CD in remission	2, 5, 6
Hanauer 1993	5‐ASA 4g/day alone	Clinical response	Uncontrolled	Active CD and CD in remission	1, 5
Hanauer 2004b	5‐ASA 3 g/day versus 6‐MP 50 mg/day versus placebo	Clinical, endoscopic and radiographic relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Howaldt 1993	5‐ASA 1.5 g/day versus 4‐ASA 1.5 g/day	Clinical relapse	Randomized controlled	CD in remission	2, 6
Klein 1995	5‐ASA 1.5 g/day versus Placebo	Endoscopic relapse	Controlled trial	CD in remission (Surgical)	2, 6
Klotz 1980	SASP versus Sulfapyridine versus Rectal 5‐ASA	Activity index, stool quality, remission rate	Randomized controlled	Active CD and UC	3, 5
Lennard‐Jones 1977	SASP versus Placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission (Medical/Surgical)	2, 6
Lichtenstein 2009a	5‐ASA alone	Clinical relapse	Prospective, uncontrolled	CD in remission	1, 2, 5, 6
Lichtenstein 2009b	5‐ASA alone	Clinical remission	Prospective, uncontrolled	Active CD	1, 5
Lochs 1991	SASP 3 g/day + CS versus Enteral Nutrition	Clinical remission	Randomized controlled	Active CD	4, 5
Lochs 2000	5‐ASA 4 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Mahmud 2001	5‐ASA 2 g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Malchow 1990	SASP + CS versus Enteral Nutrition	Clinical remission	Randomized controlled	Active CD	4, 5
Mantzaris 2003	5‐ASA 3 g/day versus Budesonide 6 mg/day	Clinical relapse and quality of life	Randomized controlled	CD in remission (Steroid‐dependent)	2, 6
Mate‐Jimenez 2000	5‐ASA 3g/day versus MTX 15 mg/week versus 6‐MP 1.5 mg/kg/day	Clinical remission and relapse	Randomized controlled	CD and UC (Steroid‐dependent)	2, 5, 6
McLeod 1995	5‐ASA 3g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Surgical)	2, 6
Modigliani 1996	5‐ASA 4g/day versus Placebo	Clinical relapse, steroid weaning	Randomized controlled	CD in remission (Steroid‐induced)	2,6
Orlando 2012	5‐ASA alone	Endoscopic recurrence	Prospective, uncontrolled	CD in remission (Surgical)	1, 2, 5, 6
Papi 2009	5‐ASA alone vs No Treatment	Clinical and surgical relapse	Retrospective	CD in remission (Surgical)	1, 2, 6
Prantera 1992	5‐ASA 2.4 g/day versus placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Rasmussen 1983	5‐ASA 1.5 g/day alone	Clinical response	Uncontrolled	Active CD	1, 5
Reinisch 2010	5‐ASA versus Azathioprine	Therapeutic failure	Duoble‐blind, Double‐dummy, Randomized controlled	CD in remission, moderate/severe endoscopic recurrence	2, 5, 6
Romano 2005	5‐ASA+omega‐3 FA versus 5‐ASA	Clinical relapse	Randomized controlled, double‐blind	CD in remission (Paediatric)	2, 4, 6
Rosen 1982 Ursing1982	SASP 3 g/day versus Metronidazole	Remission	Randomized controlled	Active CD	5
Savarino 2013	5ASA versus Azathioprine versus Adalimumab	Endoscopic and clinical recurrence	Randomized controlled	CD in remission (Surgical)	2, 5, 6
Schneider 1985	Metronidazole versus CS + SASP +/‐ Metronidazole	Clinical response	Randomized controlled	Active CD or discharging fistulae	4, 5
Schreiber 1994	5‐ASA 1.5 g/day versus 4‐ASA 1.5 g/day	Clinical relapse	Randomized controlled	CD in remission	2, 6
Singleton 1979	SASP 1 g/15 kg + CS versus CS alone	Clinical remission and response	Randomized controlled	Active CD	4
Stober 1983	SASP+CS versus Elementary Diet + SASP +/‐ CS	Laboratory parameters, body weight		Active CD (Paediatric)	2, 4, 5, 6
Sutherland 1997	5‐ASA 3g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission (Medical or Surgical)	2,6
Tao 2009	5‐ASA versus Tripterygium wilfordii	Clinical relapse	Randomized controlled	CD in remission (Surgical)	2, 5, 6
Terranova 2001	5ASA + Enteral Nutrition versus 5‐ASA + CS	Clinical improvement, biohumoral markers	Randomized controlled	Active CD and UC	4, 5
Terrin 2002	5‐ASA + CS versus Semi‐Elemental Diet	Clinical remission	Randomized controlled	Active CD	4, 5
Thomson 1995	5‐ASA 3g/day versus Placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Triantafillidis 2010	5‐ASA vs Modulen ®IBD	Clinical relapse	Randomized controlled	CD in remission	2, 5, 6
Wellman 1986	TPN + steroids with or without 5‐ASA lavage	Endotoxemia, clinical response	Randomized controlled	Active CD	3, 4, 5
Wellmann 1988	5‐ASA versus Placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission	2, 6
Wenckert 1978	SASP versus Placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission (Surgical)	2, 6
Yamamoto 2009	5‐ASA versus Azathioprine versus Infliximab	Clinical relapse	Prospective	CD in remission (Surgical)	1, 2, 5, 6
1=Inappropriate study design (Uncontrolled, open‐label), 2= Inappropriate study population (pediatric, CD in remission, severe CD), 3= Inappropriate route of drug delivery (rectal, lavage), 4= combined therapy, 5= inappropriate comparator, 6= inappropriate endpoint, 7=cross‐over studies that did not provide data prior to first crossover. Numbers in bold indicate primary reason for exclusion.

Table 1. Characteristics of Excluded Studies

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Comparison 1. Sulfasalazine versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission (CDAI <150), therapeutic response (VHI decrease >=25%) or clinical improvement Show forest plot	3	289	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.95, 2.43]

2 Induction of remission (CDAI <150) (Random Effects Model) Show forest plot	2	263	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.00, 1.89]

3 Induction of remission (CDA I<150) (Fixed Effect Model) Show forest plot	2	263	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.01, 1.90]

4 Adverse events Show forest plot	1	151	Risk Ratio (M‐H, Random, 95% CI)	2.08 [0.75, 5.80]

5 Serious adverse events Show forest plot	1	151	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.01, 8.38]

6 Withdrawal due to adverse events Show forest plot	3	289	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.26, 3.83]

Comparison 1. Sulfasalazine versus placebo

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Comparison 2. Sulfasalazine versus corticosteroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission (CDAI <150) Show forest plot	2	260	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.51, 0.91]

2 Adverse events Show forest plot	1	159	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.22, 0.82]

3 Serious adverse events Show forest plot	1	159	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 3.12]

4 Withdrawal adverse events Show forest plot	2	260	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.33, 1.59]

Comparison 2. Sulfasalazine versus corticosteroids

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Comparison 3. Sulfasalazine versus sulfasalazine and corticosteroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission Show forest plot	1	110	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.47, 0.86]

2 Withdrawal due to adverse events Show forest plot	1	110	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.05, 5.55]

Comparison 3. Sulfasalazine versus sulfasalazine and corticosteroids

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Comparison 4. Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Decrease in CDAI >=50, HBI >=2 or improvement/remission (as defined by Tvede et al) Show forest plot	3	342	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.80, 1.42]

1.1 1 g/day	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.56, 1.46]
1.2 1.5 g/day	2	107	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.87, 2.49]
1.3 2 g/day	1	115	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.60, 1.55]
2 Induction of remission (CDAI <=150 + decrease of >=50 or as defined by Tvede et al) Show forest plot	2	302	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.89, 2.40]

2.1 1 g/day	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.59, 2.82]
2.2 1.5 g/day	1	67	Risk Ratio (M‐H, Random, 95% CI)	2.16 [0.70, 6.68]
2.3 2 g/day	1	115	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.63, 3.00]
3 Adverse events Show forest plot	3	342	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.91, 1.96]

3.1 1 g/day	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.55, 2.69]
3.2 1.5 g/day	2	107	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.73, 2.24]
3.3 2 g/day	1	115	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.76, 3.11]
4 Withdrawal due to adverse events Show forest plot	3	342	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.75, 1.95]

4.1 1 g/day	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.48, 2.42]
4.2 1.5 g/day	2	107	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.56, 3.86]
4.3 2 g/day	1	115	Risk Ratio (M‐H, Random, 95% CI)	1.2 [0.57, 2.51]

Comparison 4. Controlled‐release mesalamine (1 ‐ 2 g/day) versus placebo

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Comparison 5. Controlled‐release mesalamine (4 g/day) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean change in CDAI from baseline (random‐effects model) Show forest plot	3	615	Mean Difference (IV, Random, 95% CI)	‐19.76 [‐46.22, 6.70]

2 Mean change in CDAI from baseline (fixed‐effect model) Show forest plot	3	615	Mean Difference (IV, Fixed, 95% CI)	‐17.54 [‐33.00, ‐0.08]

3 Adverse events Show forest plot	1	155	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.79, 2.57]

4 Withdrawal due to adverse events Show forest plot	1	155	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.30, 1.37]

Comparison 5. Controlled‐release mesalamine (4 g/day) versus placebo

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Comparison 6. Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission or clinical improvement Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Olsalazine (2 g/day)	1	91	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.71]
1.2 Asacol (3.2 g/day)	1	38	Risk Ratio (M‐H, Random, 95% CI)	2.70 [1.06, 6.88]
2 Induction of remission (CDAI < 150 + decrease >=70) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Asacol (3.2 g/day)	1	38	Risk Ratio (M‐H, Random, 95% CI)	2.03 [0.75, 5.45]
3 Adverse events Show forest plot	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.9 [0.68, 1.18]

4 Withdrawal due to adverse events Show forest plot	1	91	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.99, 2.24]

Comparison 6. Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) versus placebo

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Comparison 7. Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission (CDAI < or =150 with or without decrease of at least 60 points) Show forest plot	3	178	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.79, 1.36]

1.1 3 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.49, 1.85]
1.2 4 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.61, 1.64]
1.3 4 g/day microgranules	1	44	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.82, 1.92]
1.4 4.5 g/day	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.30, 1.46]
2 Adverse events Show forest plot	3	178	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.23, 1.05]

2.1 3 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.22, 1.01]
2.2 4 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.12, 0.81]
2.3 4 g/day microgranules	1	44	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.07, 0.82]
2.4 4.5 g/day	1	34	Risk Ratio (M‐H, Random, 95% CI)	1.1 [0.65, 1.87]
3 Serious adverse events Show forest plot	3	178	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.10, 1.27]

3.1 3 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.16, 4.64]
3.2 4 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.00, 1.75]
3.3 4 g/day microgranules	1	44	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.02, 1.68]
3.4 4.5 g/day	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Withdrawal due to adverse events Show forest plot	3	178	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.13, 1.15]

4.1 3 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.16, 4.64]
4.2 4 g/day	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.00, 1.75]
4.3 4 g/day microgranules	1	44	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.02, 1.68]
4.4 4.5 g/day	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.01]

Comparison 7. Delayed‐release mesalamine (3 ‐ 4.5 g/day) versus corticosteroids

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Comparison 8. Mesalamine (4 ‐ 4.5 g/day) versus budesonide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission (CDAI < or = 150) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Pentasa (4 g/day)	1	182	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.40, 0.78]
1.2 Salofalk (4.5 g/day)	1	307	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.76, 1.05]
2 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Pentasa (4 g/day)	1	182	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.93, 1.39]
2.2 Salofalk (4.5 g/day)	1	307	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.86, 1.41]
3 Serious adverse events Show forest plot	1	182	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.80, 3.25]

4 Withdrawal due to adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Pentasa (4 g/day)	1	182	Risk Ratio (M‐H, Random, 95% CI)	2.81 [1.60, 4.96]
4.2 Salofalk (4.5 g/day)	1	307	Risk Ratio (M‐H, Random, 95% CI)	2.01 [0.62, 6.55]

Comparison 8. Mesalamine (4 ‐ 4.5 g/day) versus budesonide

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Comparison 9. Mesalamine versus sulfasalazine (alone or in combination with corticosteroids)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction of remission (CDAI < 150) or clinical improvement Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Salofalk (1.5 g/day)	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.82, 1.70]
1.2 Salofalk (3.0 g/day)	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.75, 1.18]
2 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Salofalk (1.5 g/day)	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.90]
2.2 Salofalk (3.0 g/day)	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.15, 1.93]

Comparison 9. Mesalamine versus sulfasalazine (alone or in combination with corticosteroids)

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