Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review

Table 1 Meta-analyses included for induction of clinical remission in Crohn’s disease

Study	Intervention	Comparator	Follow-up	n	Induction of clinical remission, RR (95%CI)	Quality of evidence
Chande et al[23]	AZA or 6-MP	Placebo	6 wk-9 mo	380	RR 1.23 (0.97-1.55)1	Moderate
	AZA or 6-MP	MTX	6 wk-9 mo	143	RR 1.13 (0.85-1.49)1	Low
	AZA or 6-MP	5-ASA	6 wk-9 mo	156	RR 1.24 (0.80-1.91)1	Very low
	AZA	IFX	26 wk	399	RR 0.66 (0.51-0.87)1	Moderate

¹Clinical remission as measured by individual study with a validated outcome (e.g., Crohn’s Disease Activity Index score < 150 points or a Harvey-Bradshaw Index score < 3). 5-ASA: 5-aminosalicylic acid; 6-MP: 6-mercaptopurine; AZA: Azathioprine; CI: Confidence interval; IFX: Infliximab; MTX: Methotrexate; n: Number of patients; RR: Risk ratio.

Table 2 Meta-analyses included for induction of clinical remission in ulcerative colitis

Study	Intervention	Comparator	Follow-up	n	Induction of clinical remission, RR (95%CI) or OR (95%CI)	Quality of evidence
Chande et al[24]	MTX	Placebo	36 wk	67	RR 0.96 (0.58-1.59)1	Low
	MTX	6-MP	30 wk	26	RR 0.74 (0.43-1.29)2	Very low
	MTX	5-ASA	30 wk	20	RR 2.33 (0.66-3.64) 2	Very low
Baumgart et al[25]	Tacrolimus	Placebo	2 wk	63	OR 2.27 (0.35-14.75)3	High
Lasa et al[26]	Tacrolimus	Placebo	12 wk	127	RR 0.91 (0.82-1.00)4	High

¹Clinical remission defined as a Mayo clinic score ≤ 3 (or Mayo score of ≤ 2 without sigmoidoscopy results);

²Remission defined as prednisone stopped and Mayo Clinic Score < 7;

³Clinical remission [defined as Disease Activity Index (DAI) < 2 with no individual subscore > 1];

⁴Remission defined by individual studies by Truelove-Witts Score, Modified Clinical Activity Index, clinical variables and progression to colectomy, Colitis Activity Index, Lichtiger score, Mayo score for mucosal healing or DAI Score. 5-ASA: 5-aminosalicylic acid; 6-MP: 6-mercaptopurine; CI: Confidence interval; MTX: Methotrexate; n: Number of patients; OR: Odds ratio; RR: Risk ratio; DAI: Disease Activity Index.

Table 3 Meta-analyses included for maintenance of clinical remission in ulcerative colitis

Study	Intervention	Comparator	Follow-up	n	Maintenance of clinical remission, RR (95%CI)	Quality of evidence
Wang et al[27]	MTX	Placebo	36 wk	32	RR 0.64 (0.28-1.45)1	Low
	MTX	5-ASA	76 wk	9	RR 1.12 (0.06-20.71)2	Very low
	MTX	6-MP	76 wk	18	RR 0.22 (0.03-1.45)2	Very low

¹Maintenance of remission defined as a Mayo Clinic score of < 3 and off steroids.

² Maintenance of remission defined as relapse within 76 wk (defined as 7 or more in the Mayo Clinic Score). 5-ASA: 5-aminosalicylic acid; 6-MP: 6-mercaptopurine; CI: Confidence interval; MTX: Methotrexate; n: Number of patients; RR: Risk ratio.

Table 4 Meta-analyses included for induction of clinical response in Crohn’s disease

Study	Intervention	Comparator	Follow-up	n	Clinical response, RR (95%CI)	Quality of evidence
Chande et al[23]	AZA or 6-MP	Placebo	6 wk-9 mo	434	RR 1.26 (0.98-1.62)1	Moderate

¹Clinical response considered the outcomes of remission and improvement and varied from study to study making exact comparisons across studies difficult. Therefore, the definition of improvement or remission used in each study was used for data extraction. 6-MP: 6-mercaptopurine; AZA: azathioprine; CI: Confidence interval; n: Number of patients; RR: Risk ratio.

Table 5 Meta-analyses included for induction of clinical response in ulcerative colitis

Study	Intervention	Comparator	Follow-up	n	Clinical response, RR (95%CI) or OR (95%CI)	Quality of evidence
Komaki et al[28]	Tacrolimus	Placebo	2 wks (RCT)	103	RR 4.61 (2.09-10.17)1	High
Baumgart et al[25]	Tacrolimus	Placebo	2 wk	63	OR 8.66 (1.79-42.00)2	High
Lasa et al[26]	Tacrolimus	Placebo	12 wk	127	RR 0.58 (0.45-0.73)3	High
Narula et al[29]	IFX	Cyclosporine	3 mo (RCT)	412	43.8% (IFX); 41.7% (C) OR 1.08 (0.73-1.60)4	Low
	IFX	Cyclosporine	3 mo (non RCT)	801	74.8% (IFX); 55.4% (C) OR 2.96 (2.12-4.14)5	Very low

¹Clinical response defined as reduction in Disease Activity Index (DAI) ≥ 4 with improvement of all categories;

²Clinical response (partial or complete response) based on the DAI score. A complete response was defined as complete resolution of all symptoms with a zero scored for all assessments of the DAI. A partial response was defined as a reduction of more than four points on the DAI with improvement in all categories, but not a complete response;

³Clinical response defined according to each individual study, and not shown by the meta-analysis;

⁴Definitions from individual studies: Failure to respond to treatment was combined end point of the absence of clinical response at day 7 (based on Lichtiger score < 10 and at least 3 points less than baseline), relapse between day 7 and 98, absence of steroid-free remission at day 98, severe adverse event leading to treatment interruption, colectomy; response based on Powell-Tuck index ≤ 3; doubling of the Crohn's and ulcerative colitis questionnaire-32 score at 3 mo;

⁵Definitions from individual studies: Failure to respond including ongoing or worsening symptoms of bloody diarrhea, abdominal pain and persistently elevated inflammatory markers, or the development of a complication (perforation, severe hemorrhage, toxic megacolon); good response to treatment was decrease in stool frequency (< 6/d), little or no blood in feces, absence of complications; clinical remission, as per clinical symptom questionnaire used locally at this institution; being discharged from hospital without surgery or additional rescue therapy; physician global assessment of patient response—those deemed medical failure were treated with colectomy; steroid-free clinical remission (mild or inactive based on the Montreal severity score) plus no need for second rescue therapy or colectomy; modified Truelove and Witts Severity Index score decrease ≥ 4points; remission based on Colitis Activity Index ≤ 4 within 4 wk; in 5 studies, treatment response was not reported. C: Cyclosporine; CI: Confidence interval; IFX: Infliximab; n: Number of patients; OR: Odds ratio; RCT: Randomized clinical trial; RR: Risk ratio.

Table 6 Meta-analyses included for induction of mucosal healing in Crohn’s disease

Study	Intervention	Comparator	Follow-up	n	Mucosal healing, RR (95%CI)	Quality of evidence
Chande et al[23]	AZA	IFX	26 wk	214	RR 0.55 (0.33-0.94)1	Moderate

¹Mucosal healing was defined as the absence of mucosal ulceration at week 26 in patients who had confirmed mucosal ulceration at baseline. AZA: Azathioprine; CI: Confidence interval; IFX: Infliximab; n: Number of patients; RR: Risk ratio.

Table 7 Meta-analyses included for induction of mucosal healing in ulcerative colitis

Study	Intervention	Comparator	Follow-up	n	Mucosal healing, RR (95% CI)	Quality of evidence
Lasa et al[26]	Tacrolimus	Placebo	12 wk	127	RR 0.59 (0.46-0.74)1	High

¹Mucosal healing was defined as by the Mayo score for mucosal healing. CI: Confidence interval; n: Number of patients; RR: Risk ratio.

Table 8 Meta-analyses included for inflammatory bowel disease-related surgeries in ulcerative colitis

Study	Intervention	Comparator	Follow-up	N	Colectomy rate %, or OR (95% CI)	Quality of evidence
Komaki et al[28]	Tacrolimus	Placebo	2 wk (RCT)	103	0%	High
Narula et al[29]	IFX	Cyclosporine	3 mo (RCT)	385	26.6% (IFX); 26.4% (C) OR 1.00 (0.64-1.59)	Low
	IFX	Cyclosporine	3 mo (non RCT)	478	24.1% (IFX); 42.5% (C) OR 0.53 (0.22-1.28)	Very low
	IFX	Cyclosporine	12 mo (RCT)	415	34.4% (IFX); 40.8% (C) OR 0.76 (0.51-1.14)	Low
	IFX	Cyclosporine	12 mo (non RCT)	854	20.7% (IFX); 36.8% (C) OR 0.42 (0.22-0.83)	Very low

C: Cyclosporine; CI: Confidence interval; IFX: Infliximab; n: Number of patients; OR: Odds ratio; RCT: Randomized clinical trial.

Table 9 Individual studies included for induction of clinical remission in Crohn’s disease

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Induction of clinical remission
Thomsen et al[45]	Denmark, France, United Kingdom, Norway, Italy, Spain, Portugal, Greece, South Africa, Austria, Australia, and Ireland	Budesonide	Mesalamine	RCT	8 wk	182	69% (budesonide) 45% (mesalamine) (P = 0.001)1
		Budesonide	Mesalamine	RCT	16 wk	182	62% (budesonide) 36% (mesalamine) (P < 0.001)1
Pavez et al[41]	Chile	IFX	AZA	RCT	26 wk	508	0.44 (event rate IFX); 0.3 (event rate AZA)2

¹Clinical remission defined as Crohn’s Disease Activity Index (CDAI) ≤ 150;

²Clinical remission defined as CDAI less than 150 in patients who did not receive budesonide at a daily dose greater than 6 mg, or systemic corticosteroids for at least 3 wk. AZA: Azathioprine; IFX: Infliximab; n: Number of patients; RCT: Randomized clinical trial; CDAI: Crohn’s Disease Activity Index.

Table 10 Individual studies included for induction of clinical remission in ulcerative colitis

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Induction of clinical remission
Schmidt et al[30]	Germany	Tacrolimus	-	Retrospective cohort	24 mo	58	51%1
		Tacrolimus with purine analogues	-	Retrospective cohort	24 mo	79	82%1
Llaó et al[31]	Spain	IV corticosteroids	-	Retrospective cohort	3 d	110	52%2
		IV corticosteroids	-	Retrospective cohort	7 d	110	75% 2
Campbell et al[35]	UK	Cyclosporine	-	Retrospective cohort	Acute phase	76	74%3
Sood et al[33]	India	AZA	Placebo	RCT	1 yr	83	56% (AZA); 40% (placebo)4
Prieux-Klotz et al[37]	France	AZA or 6-MP		Retrospective cohort	38 mo	80	61.2%5
Yamamoto et al[38]	Japan	Tacrolimus	Anti-TNF	Retrospective	12 wk	100	40% (tacrolimus); 28% (anti-TNF); P = 0.296
Ogata et al[39]	Japan	Tacrolimus	Placebo	RCT	2 wk	62	9.4% (tacrolimus); 0% (placebo); P = 0.2387
		Tacrolimus	Placebo	RCT	12 wk	21	28.6% (tacrolimus)7
Hyde et al[44]	United Kingdom	Hydrocortisone	-	Retrospective cohort	5 d	216	61%8
		Cyclosporine	-	Retrospective cohort	4.5 d	50	56%8
Kjeldsen et al[43]	Denmark	Prednisolone	-	Retrospective cohort	6 wk	51	47% (severe disease); 80% (moderate disease)9
Meyers et al[42]	United States	ACTH	Hydrocortisone	RCT	10 d	66	44% (ACTH); 41% (Hydrocortisone)10

¹Clinical remission defined by a Lichtiger score ≤ 3;

²Clinical remission defined as mild activity or inactive disease according to the Montreal severity score, with no need for rescue treatment at day 7 after starting intravenous CS;

³Response defined as a reduction of bowel frequency to fewer than three daily and a C-reactive protein < 45 mg/L;

⁴Clinical remission defined as clinical improvement with absent of symptoms of active disease (rectal bleeding, bowel frequency) with sigmoidoscopic appearance of grade 0-1 and normal histological pattern;

⁵Clinical remission defined as a partial Mayo Clinic score ≤ 2 without any clinical subscore > 1;

⁶Clinical remission defined as a score of 0 in the clinical section (both stool frequency and rectal bleeding);

⁷Clinical remission was defined as a total DAI score ≤ 2 with an individual subscore of 0 or 1;

⁸Clinical remission defined as bowel frequency less than three stools per day, no visible blood, no fever or pain;

⁹Remission was assessed in accordance with a modified Truelove and Witts index;

¹⁰Remission defined as patient receiving no therapy or only prophylactic sulfasalazine. 6-MP: 6-mercaptopurine; ACTH: Adrenocorticotrophic hormone; AZA: Azathioprine; CI: Confidence interval; IV: Intravenous; MTX: Methotrexate; n: Number of patients; RCT: Randomized clinical trial; TNF: Tumor necrosis factor; DAI: Disease Activity Index.

Table 11 Individual studies included for maintenance of clinical remission in ulcerative colitis

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Maintenance of clinical remission
Sood et al[32]	India	AZA	-	Retrospective cohort	12 mo	111	91%1
		AZA	-	Retrospective cohort	24 mo	N/A	88%1
		AZA	-	Retrospective cohort	36 mo	N/A	76%1
		AZA	-	Retrospective cohort	48 mo	N/A	53%1
		AZA	-	Retrospective cohort	60 mo	N/A	38%1
Campbell et al[35]	United Kingdom	Cyclosporine	-	Retrospective cohort	1 yr	76	35%2
		Cyclosporine	-	Retrospective cohort	3 yr	N/A	10%2
Arts et al[36]	Belgium	Cyclosporine	-	Retrospective cohort	1 yr	34	27.8%3
		Cyclosporine	-	Retrospective cohort	3 yr	5	50%3
Hyde et al[44]	United Kingdom	Cyclosporine	-	Retrospective cohort	19 mo	50	40%4
Meyers et al[42]	United States	ACTH	Hydrocortisone	RCT	1 yr	66	37.5% (ACTH); 23.5% (hydrocortisone)5

¹Remission was defined as absence of symptoms of active disease as rectal bleeding and normal bowel frequency and hence no need for steroids for at least 6 mo;

²Maintenance of remission defined as absent of disease relapse;

³The study does not present the exact definition considered for clinical remission;

⁴Remission defined as bowel frequency less than three stools per day, no visible blood, no fever or pain;

⁵Therapeutic success was considered as a clinical remission, defined by the absence of all symptoms and the reduction of the frequency of bowel movements to two or less per day. ACTH: Adrenocorticotrophic hormone; AZA: Azathioprine; n: Number of patients; N/A: Not available; RCT: Randomized clinical trial.

Table 12 Individual studies included for induction or maintenance of clinical response in Crohn’s disease

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Clinical response
Chun et al[46]	United States	ACTH	Hydrocortisone	RCT	10 d	88	82% (ACTH; 67%-92%); 93% (hydrocortisone; 84%-99%)1

¹Clinical response evaluated by Present-Korelitz Index. ACTH: Adrenocorticotrophic hormone; n: Number of patients; RCT: Randomized clinical trial.

Table 13 Individual studies included for induction or maintenance of clinical response in ulcerative colitis

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Clinical response
Arts et al[36]	Belgium	Cyclosporine	-	Retrospective cohort	9 d	86	83.7%1
Prieux-Klotz et al[37]	France	AZA or 6-MP	-	Retrospective cohort	38 mo	80	70%2
Yamamoto et al[38]	Japan	Tacrolimus	Anti-TNF	Retrospective	12 wk	100	62% (tacrolimus); 64% (anti-TNF); P > 0.993
Ogata et al[39]	Japan	Tacrolimus	Placebo	RCT	2 wk	62	50% (tacrolimus); 13.3% (placebo); P = 0.0034
Van Assche et al[48]	Belgium	Cyclosporine 4 mg/kg	Cyclosporine 2 mg/kg	RCT	2 wk	73	84.2% (4 mg/kg); 85.7% (2 mg/kg)5
Oshitani et al[47]	Japan	Prednisolone	Methylprednisolone	Retrospective cohort	7-14 d	71	82% (prednisolone); 82% (methylprednisolone)6

¹Response defined as colectomy avoided;^{. 2}Clinical response defined by a decrease in the partial Mayo score of at least 3 points and 30% with a rectal bleeding Mayo subscore ≤ 1;

³Clinical response was defined as a decrease of at least 2 points in the clinical section (stool frequency and/or rectal bleeding);

⁴Clinical response was defined as improvement in all Disease Activity Index subscores;

⁵Clinical response was defined as a score of less than 10 at day 8 with a drop of ≥ 3 as compared with baseline;

⁶Clinical response considered as at least one of: decreased blood in stools compared with previous findings; soft or normal stool; no nocturnal defecation. 6-MP: 6-mercaptopurine; AZA: Azathioprine; n: Number of patients; RCT: Randomized clinical trial; TNF: Tumor necrosis factor.

Table 14 Individual studies included for mucosal healing in ulcerative colitis

Study	Country	Intervention	Comparator	Study design	Follow-up	N	Mucosal healing
Prieux-Klotz et al[37]	France	AZA or 6-MP	-	Retrospective cohort	38 mo	80	43.7%1
Yamamoto et al[38]	Japan	Tacrolimus	Anti-TNF	Retrospective	12 wk	73	32% (tacrolimus); 28% (anti-TNF); P = 0.862
Ogata et al[39]	Japan	Tacrolimus	Placebo	RCT	2 wk	62	43.8% (tacrolimus); 13.3% (placebo); P = 0.0123
		Tacrolimus	Placebo	RCT	12 wk	21	85.7% (tacrolimus)3
Oshitani et al[47]	Japan	Prednisolone	Methylprednisolone	Retrospective cohort	6 wk	71	78% (prednisolone); 82% (methylprednisolone)4

¹Endoscopic mucosal healing was defined by endoscopic Mayo score of 0 or 1 and ulcerative colitis endoscopic index of severity ≤ 2;

²Endoscopic healing was defined as an endoscopic score of 0 or 1;

³Mucosal healing was defined as mucosal appearance subscore of 0 or 1;

⁴Endoscopic change considers endoscopic remission (no ulcers, no erosion, no friability) and endoscopic improvement (ulcers, erosion and friability decreased compared with previous findings). 6-MP: 6-mercaptopurine; AZA: Azathioprine; n: Number of patients; RCT: Randomized clinical trial; TNF: Tumor necrosis factor.

Table 15 Individual studies included for surgeries related to Crohn’s disease

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Colectomy
Chun et al[46]	United States	ACTH	Hydrocortisone	RCT	3 yr	88	28% (both groups)

ACTH: Adrenocorticotrophic hormone; n: number of patients; RCT: Randomized clinical trial.

Table 16 Individual studies included for surgeries related to ulcerative colitis

Study	Country	Intervention	Comparator	Study design	Follow-up	n	Colectomy
Schmidt et al[30]	Germany	Tacrolimus	-	Retrospective cohort	24 mo	58	22%
		Tacrolimus with purine analogues	-	Retrospective cohort	24 mo	79	18%
Llaó et al[31]	Spain	IV corticosteroids	-	Retrospective cohort	7 d	110	15%
Moskovitz et al[34]	Belgium	Cyclosporine	-	Retrospective cohort	9.3 d	142	16.9%
		Cyclosporine	-	Retrospective cohort	1 yr	N/A	37%
		Cyclosporine	-	Retrospective cohort	4 yr	N/A	59%
		Cyclosporine	-	Retrospective cohort	6 yr	N/A	84%
		Cyclosporine	-	Retrospective cohort	7 yr	N/A	88%
Campbell et al[35]	UK	Cyclosporine	-	Retrospective cohort	7 yr		58%
Arts et al[36]	Belgium	Cyclosporine	-	Retrospective cohort	9 d	86	16.3%
		Cyclosporine	-	Retrospective cohort	1 yr	45	36%
		Cyclosporine	-	Retrospective cohort	3 yr	13	45%
Yamamoto et al[38]	Japan	Tacrolimus	Anti-TNF	Retrospective	12 wk	100	10% (tacrolimus); 16% (anti-TNF); P = 0.55
Cheifetz et al[40]	United States	Cyclosporine		Retrospective cohort	4 wk	71	15%
		Cyclosporine		Retrospective cohort	1 yr	71	39%
		Cyclosporine		Retrospective cohort	2 yr	71	42%
		Cyclosporine		Retrospective cohort	5 yr	71	46%
Gustavsson et al[49]	Sweden	Corticosteroid		Retrospective cohort	3 mo	45 (moderate)	8.9%
		Corticosteroid		Retrospective cohort	3 mo	61 (severe)	45.9%
		Corticosteroid		Retrospective cohort	20 yr	41 (moderate)	48.8%
		Corticosteroid		Retrospective cohort	20 yr	33 (severe)	33.3%
Van Assche et al[48]	Belgium	Cyclosporine 4 mg/kg	Cyclosporine 2 mg/kg	RCT	2 wk	73	13.1% (4 mg/kg); 8.6% (2 mg/kg)
Hyde et al[44]	United Kingdom	Hydrocortisone	-	Retrospective cohort	5 d	216	15.7%
		Cyclosporine	-	Retrospective cohort	19 mo	50	16%
Kjeldsen et al[43]	Denmark	Prednisolone	-	Retrospective cohort	8 mo	51	42% (severe disease); 13% (moderate disease)

IV: Intravenous; n: Number of patients; N/A: Not available; RCT: Randomized clinical trial; TNF: Tumor necrosis factor.