A. MEDLINE and CENTRAL Search Terms

Appendix 1: Search Strategies

A. MEDLINE and CENTRAL Search Terms

Boolean search for study design (Randomized Controlled Trials)

(controlled clinical trial or randomized controlled trial or meta analysis).pt.

(placebo* or random* or trial* or groups).tw.

Boolean search for population (patients with Crohn’s disease)

exp Colitis/

exp Ileitis/

exp Inflammatory Bowel Diseases/

exp Crohn Disease/

(Crohn* disease or inflammatory bowel disease* or ileitis or regional enteritis or crohn* disease or colitis).tw.

Boolean search for intervention
Aminosalicylate drugs

exp Mesalamine/

(mesalamine or mesalazine or aminosalicylate* or aminosalicylic* or 5-aminosalicylate* or 5aminosalicylate* or 5-aminosalicyclic* or 5aminosalicylic or 5-ASA or 5ASA or pentasa or olsalazine or balsalazide).tw.

(sulphasalazine* or sulfasalazine* or salazosul* or salicylazosul* or salazopyri*).tw.

Corticosteroids

Each of the terms within each of the three Boolean searches will be separated by the Boolean operator “or”. The three separate Boolean searches will be combined by the Boolean operator “and”.

B. EMBASE Search Terms

Boolean search for study design (Randomized Controlled Trials)

exp "randomized controlled trial (topic)"/ or exp controlled clinical trial/ or exp "clinical trial (topic)"/ or exp "controlled clinical trial (topic)"/

crossover procedure/

double blind procedure/

randomized controlled trial/

single blind procedure/

(((((random* or factorial* or crossover* or cross over* or cross-over* or placebo* or doubl*) adj blind*) or singl*) adj blind*) or assign* or allocat* or volunteer*).tw.

(randomized controlled trial or randomised controlled trial or clinical trial).tw.

randomized controlled trial/

clinical trial/

controlled study/

exp placebo/

Boolean search for population (patients with Crohn’s disease)

exp Crohn disease/ or exp colon Crohn disease/

exp ileitis/

exp enteritis/

(crohn disease or crohn's disease).tw.

ileitis.tw.

inflammatory bowel disease.tw.

regional enteritis.tw.

Boolean search for intervention

Aminosalicylate drugs

expaminosalicylic acid/

expmesalazine/

expolsalazine/

expbalsalazide/

(aminosalicylic acid or aminosalicylate).tw.

(mesalazine or mesalamine).tw.

(olsalazine or balsalazide).tw.

(sulphasalazine* or sulfasalazine* or salazosul* or salicylazosul* or salazopyri*).tw.

Corticosteroids

Each of the terms within each of the three Boolean searches will be separated by the Boolean operator “or”. The three separate Boolean searches will be combined by the Boolean operator “and”.

Appendix 2: JAGS coding

model{

#Loop through studies

for(i in 1:NS) {

#Adjustment for multi-arm trials is zero for control arm

w[i,1] <- 0

#Treatment effect is zero for control arm

delta[i,1] <- 0

#Vague priors for trial baselines

mu[i] ~ dnorm(0,0.0001)

#Binomial likelihood with logit link

for(k in 1:na[i]){

x[i,k] ~ dbin(p[i,k],n[i,k])

logit(p[i,k]) <- mu[i] + delta[i,k]

#Model fit

#Expected value of the numerators

xhat[i,k] <- p[i,k] * n[i,k]

#Deviance contribution

dev[i,k] <- 2 * (x[i,k] * (log(x[i,k])-log(xhat[i,k]))

+ (n[i,k]-x[i,k]) * (log(n[i,k]-x[i,k]) - log(n[i,k]-xhat[i,k])))

}

#Summed residual deviance contribution for each trial

resdev[i] <- sum(dev[i,1:na[i]])

#Trial-specific log(OR) distributions (random effect)

for(k in 2:na[i]){

delta[i,k] ~ dnorm(md[i,k], taud[i,k])

#Mean of log(OR) distributions

md[i,k] <- d[t[i,k]] - d[t[i,1]] + sw[i,k]

#Precision of log(OR) distributions

taud[i,k] <- tau*2*(k-1)/k

#Adjustment for multi-arm RCTs

w[i,k] <- (delta[i,k] - d[t[i,k]] + d[t[i,1]])

#Cumulative adjustment for multi-arm RCTs

sw[i,k] <- sum(w[i,1:k-1])/(k-1)

}

#Total residual deviance

totresdev <- sum(resdev[])

#Priors for treatment effects

d[1] <- 0 # treatment effect is zero for reference treatment

for(k in 2:NT){

d[k] ~ dnorm(0,0.0001)

}

#All pairwise treatment effects

#Probability that each treatment is superior to every other treatment

for(i in 1:NT) {

for (j in 1:NT) { lor[i,j] <- d[i] - d[j]

log(OR[i,j]) <- lor[i,j]

better[i,j] <- step(OR[i,j]-1)

}}

Appendix Table 1: Characteristics of the excluded randomized control trials on the effects of mesalamine on the induction of remission for patients with Crohn’s Disease

Study / Reason for Exclusion
Cochrane Review: Mesalamine Induction(4)
Crohns III 1997(33) / Outcome not Remission
Mahida 1990(34) / Outcome not Remission
Maier 1985(35) / Outcome not Remission
Maier 1990(36) / Excluded Active Comparator (mesalamine vs mesalamine+sulphasalazine)
Rasmussen 1987(37) / Does not use CDAI
Rijk 1991(38) / Excluded Active Comparator (sulphasalazine vs sulphasalazine +corticosteroids)
Saverymuttu 1986(39) / Final values not given.
Singleton 1994(40) / Final values not given.
Van Hees 1981(41) / Outcome not Remission
Wright 1995(42) / Outcome not Remission
Cochrane Review: Budesonide Induction(8)
Bar-Meir 1998(20) / Excluded Active Comparator
Campieri 1997(21) / Excluded Active Comparator
D’Haens 1998(43) / No definition of remission provided
Escher 2004(44) / Excluded Active Comparator
Gross 1996(23) / Excluded Active Comparator
Irvine 2000(45) / Secondary analysis (quality of life data only) of included RCT(22)
Levine 2003(46) / Excluded Active Comparator
Rutgeerts 1994(24) / Excluded Active Comparator
Thomsen 2002(47) / Secondary analysis (quality of life data only) of included RCT(16)
Tursi 2006(26) / Excluded Active Comparator
Van Ierssel 1995(27) / Excluded Active Comparator
Cochrane Review: Corticosteroid Induction(5)
Scholmerick 1990(48) / Does not use CDAI
Singleton 1979 / Secondary analysis (Adverse Reactions) of included RCT
Winship 1979 / Secondary analysis (Methods) of included RCT

Appendix Table 2: Quality assessment of included randomized control trials on the effects of mesalamine, sulfasalazine, corticosteroids, or budesonide on the induction of remission for patients with Crohn’s Disease

Selection Bias / Performance and Detection Biases / Attrition Bias / Reporting bias
Study / Random Sequence Generation / Allocation Concealment / Blinding / Incomplete Outcome Data / Selective Reporting / Other bias
Sulfasalazine versus Placebo
Malchow1984(13) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk
Summers1979(15) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk
Mesalamine versus Placebo
Crohn’s II 2011(12) / Unclear / Unclear / Unclear / Unclear / Unclear / Unclear
PEACE Study 2012(11) / Unclear / Unclear / Low risk / Low risk / Low risk / Low risk
Singleton 1993(14) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Tremaine 1994(17) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Budesonide versus Placebo
Greenberg 1994(22) / Low risk / Low risk / Low risk / Low risk / Low risk / Low risk
Suzuki 2013(19) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Tremaine 2002(25) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Budesonide (Low versus High Dose)
Herfarth 2004(32) / Low risk / Low risk / Low risk / Low risk / Low risk / Low risk
Budesonide versus Mesalamine
Thomsen 1998(16) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Tromm 2011(18) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Budesonide versus Corticosteroids
Bar-Meir 1998(20) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Campieri 1997(21) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Gross 1996(23) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Rutgeerts 1994(24) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Tursi 2006(26) / Unclear / Unclear / High riska / Low risk / Low risk / Low risk
Van Ierssel 1995(27) / Unclear / Unclear / Low risk / Unclear / Low risk / Low risk
Mesalamine/sulfasalazine versus corticosteroids
Gross 1995(28) / Unclear / Unclear / Low risk / Low risk / Low risk / Low risk
Malchow1984(13)
(sulfasalazine) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk
Martin 1990(29) / Unclear / Unclear / Low risk / Low risk / Low risk / Low risk
Prantera 1999(30) / Low risk / Unclear / Low risk / Low risk / Low risk / Low risk
Summers1979(15)
(sulfasalazine) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk
Corticosteroids versus placebo
Malchow1984(13) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk
Summers1979(15) / Unclear / Low risk / Low risk / Low risk / Low risk / Low risk

aOpen label study

Appendix Table 3: Treatment rankings for induction of remission

Average ranking (1=best, 5=worst)
Median (95% credible interval)
Placebo / 6 (5 to 7)
Low dose Mesalamine / 6 (3 to 7)
High dose Mesalamine / 3 (3 to 5)
Sulfasalazine / 5 (3 to 7)
Low dose Budesonide / 5 (3 to 7)
High dose Budesonide / 2 (1 to 3)
Corticosteroid / 1 (1 to 2)

Appendix Table 43: Results of sensitivity analysis of network meta-analysis using alternate cut points for the dosing of mesalamine and budesonide for the induction of remission of patients with Crohn’s disease

Intervention / COMPARATOR
Odds ratio (95% Credible interval)*
Probability intervention superior to comparator
Placebo / <2g Mesalamine / 2-4g Mesalamine / >4g Mesalamine / 3 or 6mg Budesonide / 9mg Budesonide / 15 or 18mg Budesonide / Sulfasalazine
<2g Mesalamine / 1.22
(0.46, 3.13)
66% / -
2-4g Mesalamine / 2.01*
(1.24, 3.38)
>99% / 1.65
(0.69, 4.13)
88% / -
>4g Mesalamine / 1.84
(0.75, 3.99)
92% / 1.52
(0.41, 4.91)
75% / 0.92
(0.34, 2.09)
42% / -
3 or 6mg Budesonide / 1.53
(0.69, 3.28)
86% / 1.26
(0.37, 4.07)
65% / 0.76
(0.31, 1.78)
26% / 0.83
(0.31, 2.42)
36% / -
9mg Budesonide / 3.03*
(1.85, 4.73)
>99% / 2.49
(0.89, 6.85)
96% / 1.51
(0.83, 2.54)
92% / 1.64
(0.82, 3.60)
93% / 1.97
(0.95, 4.12)
97% / -
15 or 18mg Budesonide / 3.36*
(1.63, 6.83)
>99% / 2.76
(0.87, 9.01)
96% / 1.66
(0.73, 3.73)
89% / 1.83
(0.72, 5.22)
90% / 2.18*
(1.02, 4.80)
98% / 1.11
(0.58, 2.17)
63% / -
Sulfasalazine / 1.53
(0.76, 3.01)
89% / 1.26
(0.40, 3.94)
66% / 0.76
(0.33, 1.65)
24% / 0.83
(0.32, 2.38)
35% / 1.00
(0.37, 2.73)
50% / 0.50
(0.24, 1.07)
4% / 0.46
(0.18, 1.18)
5% / -
Corticosteroids / 3.72*
(2.24, 5.89)
>99% / 3.05*
(1.09, 8.41)
98% / 1.84*
(1.03, 3.17)
98% / 2.01
(0.97, 4.66)
97% / 2.42*
(1.08, 5.51)
98% / 1.22
(0.83, 1.84)
86% / 1.11
(0.52, 2.29)
61% / 2.44*
(1.21, 4.82)
>99%

Appendix Table 54: Results of sensitivity analysis of network meta-analysis using combined doses of mesalamine and budesonide for the induction of remission of patients with Crohn’s disease

Intervention / COMPARATOR
Odds ratio (95% Credible interval)*
Placebo / Mesalamine / Sulfasalazine / Budesonide
Mesalamine / 1.84*
(1.25, 2.77)
>99% / -
Sulfasalazine / 1.52
(0.82, 2.68)
92% / 0.83
(0.42, 1.57)
26% / -
Budesonide / 2.90*
(1.98, 4.30)
>99% / 1.57*
(1.06, 2.32)
99% / 1.91*
(1.04, 3.61)
98% / -
Corticosteroid / 3.57*
(2.40, 5.41)
>99% / 1.94*
(1.28, 2.90)
>99% / 2.35*
(1.34, 4.31)
>99% / 1.23
(0.88, 1.73)
90%

Appendix Table 65: Results of sensitivity analysis of network meta-analysis using only studies which define lower and upper limits for CDAI ranges (i.e., CDAI 150-4500) for the induction of remission of patients with Crohn’s disease

Intervention / COMPARATOR
Odds ratio (95% Credible interval)*
Probability intervention superior to comparator
Placebo / Low dose Mesalamine / High dose Mesalamine / Sulfasalazine / High dose Budesonide
Low dose Mesalamine / 1.10
(0.41, 3.05)
59%
High dose Mesalamine / 2.23*
(1.15, 4.16)
99% / 2.00
(0.73, 5.33)
93% / -
Sulfasalazine / 1.76
(0.61, 4.83)
88% / 1.58
(0.39, 6.26)
77% / 0.79
(0.26, 2.36)
32% / -
High dose Budesonide / 3.20*
(1.59, 6.27)
>99% / 2.91
(0.93, 8.37)
97% / 1.45
(0.82, 2.52)
91% / 1.82
(0.61, 5.53)
88% / -
Corticosteroid / 3.31*
(1.62, 6.48)
>99% / 2.98
(0.96, 8.62)
97% / 1.49
(0.82, 2.66)
92% / 1.90
(0.67, 5.26)
91% / 1.03
(0.57, 1.82)
55%

Appendix Table 76: Results of sensitivity analysis of network meta-analysis removing sulfasalazine and corticosteroids from the analysis of the induction of remission of patients with Crohn’s disease

Intervention / COMPARATOR
Odds ratio (95% Credible interval)*
Probability intervention superior to comparator
Placebo / Low dose Mesalamine / High dose Mesalamine / Low dose
Budesonide
Low dose Mesalamine / 0.99
(0.38, 2.66)
49%
High dose Mesalamine / 1.83*
(1.03, 3.18)
98% / 1.85
(0.68, 4.74)
91% / -
Low dose Budesonide / 1.57
(0.65, 3.74)
86% / 1.60
(0.44, 5.45)
79% / 0.86
(0.37, 2.17)
35% / -
High dose Budesonide / 3.23*
(1.83, 5.79)
>99% / 3.26*
(1.13, 9.16)
98% / 1.77
(0.99, 3.24)
97% / 2.06*
(0.96, 4.52)
97%

Appendix Table 87: PRISMA Checklist

Section/topic / Item # / Checklist item / Reported on page #
TITLE
Title / 1 / Identify the report as a systematic review, meta-analysis, or both. / 1
ABSTRACT
Structured summary / 2 / Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. / 6
INTRODUCTION
Rationale / 3 / Describe the rationale for the review in the context of what is already known. / 8
Objectives / 4 / Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). / 9
METHODS
Protocol and registration / 5 / Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. / 9
Eligibility criteria / 6 / Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. / 10
Information sources / 7 / Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. / 9
Search / 8 / Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. / 9 (Appendix 1)
Study selection / 9 / State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). / 9 and 10
Data collection process / 10 / Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. / 10
Data items / 11 / List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. / 10
Risk of bias in individual studies / 12 / Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. / 10
Summary measures / 13 / State the principal summary measures (e.g., risk ratio, difference in means). / 10 and 11
Synthesis of results / 14 / Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. / 10 and 11
Risk of bias across studies / 15 / Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). / 10
Additional analyses / 16 / Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. / 12
RESULTS
Study selection / 17 / Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. / 12 (Figure 1)
Study characteristics / 18 / For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. / 12 (Table 1)
Risk of bias within studies / 19 / Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). / 12(Appendix Table 2)
Results of individual studies / 20 / For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. / (Table 1)
Synthesis of results / 21 / Present results of each meta-analysis done, including confidence intervals and measures of consistency. / 13 and 14 (Table 2 and 3)
Risk of bias across studies / 22 / Present results of any assessment of risk of bias across studies (see Item 15). / 12and 15 (Appendix Table 2)
Additional analysis / 23 / Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). / 13 and 14 (Appendix Table 3 - 6)
DISCUSSION
Summary of evidence / 24 / Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). / 14
Limitations / 25 / Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). / 16
Conclusions / 26 / Provide a general interpretation of the results in the context of other evidence, and implications for future research. / 16
FUNDING
Funding / 27 / Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. / 2