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

Wee‐Chian Lim; Stephen Hanauer

doi:10.1002/14651858.CD008870

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Figure 1

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

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Figure 2

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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).

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Analysis 2.1

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

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Analysis 3.1

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

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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 5.1

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

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Analysis 6.1

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

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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 8.1

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

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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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Table 1. Characteristics of Excluded Studies

Study ID	Comparators	Endpoint	Study design	Patient Population	Exclusion reasons
Anonymous 1990	5‐ASA 1.5 g/day versus placebo	Clinical relapse	Randomized controlled	CD in remission (medical/surgical)	2, 6
Anonymous 1985	SASP 1 g/15 kg /day alone	Clinical response	Uncontrolled	Active CD	1, 5
Anthonisen 1974	SASP (1.5 g for 3 days followed by 3 g/day) versus placebo	Clinical improvement	Double‐blind placebo controlled cross‐over study	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
Barreiro 1991	5‐ASA 4 g/day alone	Clinical response, side effects	Uncontrolled	Active CD	1, 5
Bayerdorffer 1988	5‐ASA alone	Clinical response and relapse	Uncontrolled	Active CD and UC (followed by maintenance)	1, 5
Bergman 1976	SASP + CS versus no treatment	Clinical relapse	Randomized controlled	CD in remission (surgical)	2, 4, 6
Bresci 1991	5‐ASA 1.6 g/day versus no specific therapy	Clinical relapse	Non‐random controlled	CD in remission	2, 6
Bresci 1994	5‐ASA 2.4 g/day versus no specific therapy	Clinical relapse	Randomized controlled	CD in remission (medical)	2, 6
Bresci 2000	All on 5‐ASA only; location of initial disease	Clinical and endoscopic relapse	Prospective	CD in remission	1, 2, 5, 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
Busam 1996	5‐ASA 4 g/day alone or with CS, azathioprine, metronidazole, enteral nutrition.	Clinical response	Retrospective	Active CD, IC and UC.	1, 2, 4, 5
Campbell 2001	5‐ASA + azathioprine versus azathioprine alone	Clinical relapse	Retrospective	CD and UC in remission with azathioprine for 6 months	1, 2, 4, 5, 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 4 g/day	Clinical and endoscopic relapse	Randomized controlled	CD in remission (surgical)	2, 6
Cezard 2003	5‐ASA versus placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission (pediatric)	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
Domenech 2004	5‐ASA versus azathioprine	Clinical and endoscopic relapse	Retrospective	CD in remission (surgical)	1, 2, 5, 6
Ewe 1976	SASP versus placebo	Relapse	Double‐blind	CD in remission	2, 6
Ewe 1989	SASP versus placebo	Clinical relapse	Randomized controlled	CD in remission (surgical)	2, 6
Faber 1993	Asacol +/‐ other medications	Clinical and endoscopic response, relapse	Uncontrolled	Active and inactive CD and UC	1, 4, 5,
Fiasse 1980	SASP+CS +/‐ azathioprine	Clinical response	Uncontrolled	Active CD	1, 4, 5, 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 1980	SASP, CS and azathioprine in various combinations	Clinical and radiological response	Uncontrolled	Active CD	1, 4, 5
Griffiths 1993	5‐ASA 50 mg/kg versus placebo	Change in CDAI, VHI	Randomized controlled	Active small intestinal CD (pediatric)	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
Krook 1981	Metronidazole versus SASP	Effect on fecal flora	Uncontrolled	CD	1, 5, 6
Krook 1981	Metronidazole or SASP	Effect on CDAI and orosomucoid in relation to effect on fecal flora	Uncontrolled	CD	1, 6
Lennard‐Jones 1977	SASP versus placebo	Clinical relapse	Double‐blind placebo‐controlled	CD in remission (medical/surgical)	2, 6
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
Maier 1982	5‐ASA 0.5 g tid suppository	Clinical remission	Uncontrolled	Active CD and UC	1, 3, 5
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
May 1987	5‐ASA	Clinical response	Uncontrolled	CD and UC	1, 5
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
Nakshabendi 1992	5‐ASA versus SASP	Clinical relapse	Retrospective	CD and UC in remission	1, 2, 6
Nichols 1991	5‐ASA 1.6 to 4.8 g/day alone	Clinical response and maintenance remission	Uncontrolled	Active and inactive CD and UC	1, 5
Nos 2000	5‐ASA 3g/day versus azathioprine 50 mg/day	Clinical and morphologic relapse	Controlled	CD in remission (surgical)	2, 5, 6
Parlak 2000	5‐ASA+CS versus 5‐ASA + antibiotics	Clinical remission and response	Retrospective	Active CD	1,4,5
Piodi 1991	5‐ASA 3 g/day alone	Clinical response	Uncontrolled	Active CD	1, 5
Prantera 1992	5‐ASA 2.4 g/day versus placebo	Clinical relapse	Randomized controlled	CD in remission	2, 6
Rosen 1982 Ursing1982	SASP 3 g/day versus metronidazole	Remission	Randomized controlled	Active CD	5
Rasmussen 1983	5‐ASA 1.5 g/day alone	Clinical response	Uncontrolled	Active CD	1, 5
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
Singleton 1995	ASA 1, 2 or 4 g/day versus placebo	Quality of life	Randomized controlled	Active CD	6, repeat study
Stober 1983	SASP+CS versus elementary diet + SASP +/‐ CS	Laboratory parameters, body weight		Active CD (pediatric)	2, 4, 5, 6
Sutherland 1997	5‐ASA 3g/day versus placebo	Clinical relapse	Randomized controlled	CD in remission (medical or post‐op)	2,6
Terranova 2001	5ASA+ enteral nutrition versus 5ASA+ CS	Clinical improvement, biohumoral markers	Randomized controlled	Active CD and UC	4, 5
Thomsen 2002	5‐ASA 4g/day versus budesonide 9 mg qd	Quality of life	Randomized controlled	Active CD	6, repeat study
Thomson 1995	5‐ASA 3g/day versus placebo	Clinical relapse	Randomized controlled	CD in remission	2, 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
West 1974	SASP alone	Effect on fecal flora	Uncontrolled	CD and proctocolitis	1, 5, 6
Winterkamp 2000	5‐ASA 4.5 g/day + oligopeptide diet versus CS	CDAI and quality of life	Randomized controlled	Active CD	4
Wong 2003	Pentasa 4 g/day (switched from Asacol 2.4 g/day)	Clinical response	Uncontrolled	Active CD (not responding to Asacol)	1, 5
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

Table 1. Characteristics of Excluded Studies

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Table 2. Methodological Quality of Included Studies

Study ID	Study Design	Randomization	Concealed Allocation	Double Blind	Identical Placebo	Reasons for withdrawal clearly stated	Quality of study
Van Hees 1981	Parallel group	Yes	Unclear	Yes	Yes	No	3
Summers 1979	Parallel group	Yes	Adequate	Yes	Yes	No	4
Malchow 1984	Parallel group	Yes	Adequate	Yes	Yes	No	4
Rijk 1991	Parallel group	Yes	Unclear	Yes	Yes	No	3
Saverymuttu 1986	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Rasmussen 1987	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Mahida 1990	Parallel group	Yes	Adequate	Yes	Yes	Yes	5
Singleton 1993	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Singleton 1994†	Parallel group	Yes	Unclear	Yes	‐	‐	‐
Crohn's III 1997†	Parallel group	Yes	Unclear	Yes	‐	‐	‐
Tremaine 1994	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Wright 1995	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Maier 1985	Parallel group	Yes	Unclear	No	No	No	1
Maier 1990	Parallel group	Yes	Unclear	No	No	No	1
Schölmerich 1990	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Martin 1990	Parallel group	Yes	Unclear	Yes	No	Yes	3
Gross 1995	Parallel group	Yes	Unclear	Yes	Yes	Yes	4
Prantera 1999	Parallel group	Yes	Adequate	Yes	Yes	Yes	5
Thomsen 1998	Parallel group	Yes	Adequate	Yes	Yes	Yes	5
† Study has not been fully published

Table 2. Methodological Quality of Included 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)	1.51 [0.97, 2.35]

2 Induction of remission (CDAI <150) Show forest plot	2	263	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.02, 1.87]

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)	0.66 [0.53, 0.81]

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]

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]

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 baseline CDAI (Random effects model) Show forest plot	3	615	Mean Difference (IV, Random, 95% CI)	‐19.76 [‐46.22, 6.70]

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

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

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Comparison 6. 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]

Comparison 6. 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]

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

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Comparison 8. Controlled‐release mesalamine (4 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	1	182	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.40, 0.78]

Comparison 8. Controlled‐release mesalamine (4 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)	0.85 [0.59, 1.22]
1.2 Salofalk (3.0 g/day)	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.85, 1.33]

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

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