Use of the tumor necrosis factor-blockers for Crohn's disease

Table 1 The general biological properties of tumor necrosis factor blockers in clinical practice

Pro- or anti-apoptotic effects1

↑ Adhesion molecules on endothelial cells

↑ Epithelial permeability

↑ Antigen-stimulated B-cell proliferation and differentiation

IL-2R production1

↑ IL-2 dependent production of IFN-γ

↑HLA-DR gene expression

¹Represent the data are increased. IFN-γ: Intracellular interferon-γ; IL: Interleukin.

Table 2 Individual biological properties of tumor necrosis factor blockers

IFX

High sensitivity and specificity for binding to both sTNF and tmTNF

2-3 IFX molecules bind to each TNF trimer, preventing TNF binding to cellular receptors, and reversing the actions of TNF

The TNF trimer complexes are biologically inactive and are thought to be cleared by the hepatic reticuloendothelial system

Most IFX is in the vascular compartment

No systemic accumulation

Clearance of IFN is slowed by MTX and is ATI

The VOD at steady state is independent of dose

VOD and clearance are not affected by patient age or weight. The effect of liver or kidney disease is unknown

Does not produce a generalized suppression of the body’s immune system

Response to IFX is affected by CRP polymorphisms

Linear relationship between dose and serum concentration of IFX

Serum concentration is correlated with clinical response (in at least persons with rheumatoid arthritis)

Reductions in IL-10 levels also correlate with improvement in clinical activity, and FGF and improvement in perianal disease

For the 5 mg/kg dose, the median terminal half-life (t) is 10.9 d1

↓ Cells expressing TNF, IL-10, IFN-γ

↓ Cells staining for CD4, CD5, CD6, MMP-9

↓ TNF levels (that are ↑ in serum and diseased mucosa in CD)

↓ ICAM-1

↓ Lamina propria T-lymphocytes and peripheral blood monocytes

↓ Growth hormone resistance

↓ Markers of bone reabsorption, ↑ markers of bone formation

ADA

Forms high molecular weight complexes with human TNF (600-5000 kDa)

Linear relation between dose and serum concentration

Serum concentration is correlated with clinical response

Mean serum t is 10-20 d

Clearance is slowed by MTX, and is accelerated by ATA

Certolizumab pegol

Lacks IgG Fc domain, and thus does not fix lysed cells or complement

The Fab’ component of CER contains a free cysteine residue to the hinge region, which provides site-specific attachment of the PEG to the Fab’ at a site well removed from the antigen binding site

The retention time of protein conjugates in the blood is increased by pegylation, and immunogenicity is reduced. Pegylation increases in the half-life (t½) of the antibody fragment, so dosing may be less frequent

The half-life of CER in healthy volunteers is 313 h

Site-specific pegylation of the Fab’ fragment of CER is directed to a site well away from the antigen-binding region. In this way, the conjugate has the same high affinity of the TNF as the tmTNF and sTNF without the pegylation

Does not cause apoptosis of lymphocytes and monocytes, and antibodies to IFX (ATI) do not cross-react with CER

Accumulates preferentially in inflamed rather than in non-inflamed tissue

Has a greater affinity for sTNFs than do IFX or ADA

Has twice the neutralizing potency as IFX or ADA for sTNFα

Has the same neutralizing potency as IFX and ADA for tnTNFα, and occurs through p55/p75 TNFR

Anti-CER antibodies levels are low, and do not affect the efficacy of CER

Does not cross-react with ATI (antibodies to IFX)

Has a linear pharmacokinetic profile

Bioavailability of subcutaneously administered CER is almost 100%

Does not lyse cells, cause compliment-dependant cytotoxicity, antibody-dependant cell-mediated cytotoxicity, apoptosis of activated monocytes or lymphocytes or necrosis of neutrophils

¹Represent the counts or concentration is decreased. IFX: Infliximab; TNF: Tumor necrosis factor; MTX: Methotrexate; ATI: Accelerated by antibodies to IFX; VOD: Volume of distribution; CRP: C-reactive protein; FGF: Fibroblast growth factor; IFN-γ: Intracellular interferon-γ; IL: Interleukin; MMP-9: Metalloproteinases; ADA: Adalimumab; ATA: Antibodies to ADA; ICAM-1: Intracellular adhesion molecule-1; PEG: Polyethylene glycol; CER: Certolizumab; CD: Crohn’s disease; TNFR: TNF receptor.

Table 3 Comparison of in vitro properties of different tumor necrosis factor-α blockers in clinical practice for inflammatory bowel disease

Agent	Binds	Mediates		Increases proportion of apoptotic cells	Inhibits cytokine production	Effective in IBD patients
	TNF	CDC	ADCC
Infliximab	Yes	Yes	Yes	Yes	Yes	Yes
Etanercept	Yes	Yes	Yes	Yes	No	No
Adalimumab	Yes	Yes	Yes	Yes	Yes	Yes
Certolizumab pegol	Yes	No	No	No	Yes	Yes

TNF: Tumor necrosis factor; ADCC: Antibody-dependent cell-mediated cytotoxicity; CDC: Complement-dependent cytotoxicity; IBD: Inflammatory bowel disease.

Table 4 Management of hepatitis B virus infection in inflammatory bowel disease patient being considered for tumor necrosis factor-α blockers therapy

Serology	Management
HBsAg+, LE ↑	Treat HBV
HbsAg+, normal LE	Vaccinate for HBV; monitor LE and HBV-DNA
HbsAg-	Vaccinate for HBV
Consider giving a combined vaccination for HAV-HBV	Measure anti-HBs-Ab titer 1 mo after third injection to determine adequacy of response; additional doses may be necessary

LE: Liver enzymes; HBV: Hepatitis B virus; HAV: Hepatitis A virus; HBsAg: Hepatitis B surface antigen.

Table 5 Goals of therapy in Crohn's disease

Induce and maintain remission off steroids

Improve patient’s quality of life

Reduced risk of need for surgery or hospitalization

Reduce risk of development of adenocarcinoma/lymphoma

Maintain mucosal healing as a possible predictor or surrogate marker of better future disease outcome

Acceptable efficacy/safety balance

Table 6 Predictors of good response to tumor necrosis factor-α blockers

Luminal

Short history of CD

Less severe disease

Isolated colonic disease

Inflammatory CD[46-49]

No previous abdominal surgery

Use shortly after ileocolonic resection

CRP > 5 mg/L (76% vs 46% response to TNFB), or ↑ CRP returning to normal detectable through serum TNFB (IFX) levels. CRP concentrations are inversely correlated with the rates of placebo response[50]

Non-smoking

Fistulizing

Perhaps for response with rectovaginal fistula

TNFB: Tumor necrosis factor-α blocker; CD: Crohn's disease; CRP: C-reactive protein; IFX: Infliximab.

Table 7 Therapeutic gain for single dose infliximab for induction Crohn's disease: Response and remission (%)

Assessment week	IFX (mg/kg)			PL	Therapeutic gain
	5	10	20
Response
2	73	52	53	17	56-35-36
4	81	50	65	17	64-33-48
12	48	29	46	12	36-17-34
Remission
2	40	22	22	4	36-18-18
4	50	26	26	4	46-22-22
12	30	18	25	8	22-10-17

PL: Placebo; IFX: Infliximab.

Table 8 Comparison of tumor necrosis factor-α blockers for Crohn's disease remission and fistula closure

	IFX (mg/kg)	ADA (mg)	CER (mg)
Remission (26-30 wk)	42	43	48
Fistula closure	36[78]	32	54

CER: Certolizumab; IFX: Infliximab; ADA: Adalimumab.

Table 9 Therapeutic gain for adalimumab induction of response and remission (%)

Study	Assessment week	ADA1	ADA2	ADA3	PL	Therapeutic gain
Gain	Response (CDAI ↓≥ 100 pts)
	1	-	-	20	12	8
	2	-	-	37	18	19
	4	-	-	38	25	13
	Remission
	1	-	-	6	4	2
	2	-	-	21	6	15
	4	-	-	21	7	14
(Classic I)	Response (CDAI ↓≥ 100 pts)
	1	23	25	21	16	7-9-5
	2	31	37	31	15	16-22-16
	4	34	40	50	25	9-15-25
	Remission
	1	16	13	16	7	9-6-9
	2	14	20	24	14	0-6-10
	4	18	24	36	12	6-12-24
(Classic I)	Response (CDAI ↓≥ 70 pts)
	1	-	-	6	4	2
	2	-	-	21	6	15
	4	-	-	21	7	14
	Response
	1	37	40	32	24	13-16-8
	2	44	55	45	30	14-25-15
	4	54	59	59	37	17-22-22

¹40 mg at week 0, 20 mg at week 2;

²80 mg at week 0, 40 mg at week 2;

³160 mg at week 0, 80 mg at week 2. PL: Placebo; CDAI: Crohn’s disease activity index; ADA: Adalimumab.

Table 10 Meta-analysis of efficacy and safety of anti-tumor necrosis factor α antibodies vs placebo (4 wk to 12 wk) in inducing remission in active luminal Crohn’s disease

Treatment	Outcome (RR of remission not achieving)
All biological vs PL	RR = 0.87; 95%CI: 0.80-0.94; NNT = 8 (95%CI: 6-17)
IFX vs PL1	RR = 0.68; 95%CI: 0.52-0.90, I2 = 78%, P = 0.01; NNT = 4 (95%CI: 3-7)
ADA vs PL	RR = 0.85; 95%CI: 0.79-0.91, I2 = 0%, P = 0.99; NNT = 7 (95%CI: 5-12.5)
CER vs PL	RR = 0.95; 95%CI: 0.90-1.01, I2 = 0%, P = 0.62
Natalizumab vs PL	RR = 0.88; 95%CI: 0.83-0.94, I2 = 0%, P = 0.72
Adverse effects
	No statistically significant difference in the incidence of adverse events was detected with TNFB vs placebo (RR of experiencing any adverse event, including infusion or injection site reactions = 0.99; 95%CI: 0.90-1.08
	With anti–α4–integrin antibodies (natalizumab) vs PL, significantly more patients reported headache (compared with placebo: RR = 1.23; 95%CI: 1.03 to 1.47, I2 = 0%)
	With NAT there were trends towards more infusion reactions (RR = 1.41; 95%CI: 0.94 to 2.10, I2 = 0%) and infections (RR = 1.12; 95%CI: 0.97 to 1.30, I2 = 0%)
	Number needed to harm with NAT = 17 (95%CI: 9-71)

Independent data extraction was undertaken by two reviewers, and discrepancies checked and resolved intention-to-treat. Analysis and pooled data with a random effects model was used, including the reporting of the search strategy, inclusion criteria, and data extraction processes.

¹Note that when the Sonic trail was excluded from analysis, there was no statistically significant difference between IFX vs placebo. RR: Risk ratio; IFX: Infliximab; ADA: Adalimumab; CER: Certolizumab; PL: Placebo; CI: Confidence interval; TNFB: Tumor necrosis factor-α blockers; NAT: Natalizumab; NNT: Needed to treat.

Table 11 Mechanisms which are speculated to be the cause of primary non-response

Lack of response may be due to different immunoinflammatory mechanism(s)[63]

A differential role of TNFα in certain stages of disease

Individual differences in drug metabolism and elimination, drug binding in serum or tissues based on disease activity level[27,148]

The presence of innate anti-TNFα antibodies that may exhibit greater neutralizing activity in non-responders[175]

Absence of inflammation accounting for clinical symptoms

Unidentified, genetic or pharmacogenetic or serological backgrounds of individual patients[24,176-179]

Individual differences in bioavailability and pharmacokinetics, leading to inadequate concentrations of a biologic secondary to immunogenicity (neutralizing or non-neutralizing antibodies, or unmeasured or unknown antibody) or other factors that increase drug clearance (decreased circulation half -life and possible high consumption in severe disease)[27,128]

TNFα: Tumor necrosis factor-α.

Table 12 Secondary failure rates

Maintenance of response month (%)	Loss of response (%)	Loss of response per month (%)
13 (64)	36	2.8
55 (63)	37	0.7
28 (78)	22	0.8

In another long-term maintenance study, the percentage of Crohn's disease patients who maintained response declined over time: 30 wk, 83%; 54 wk, 64%; 108 wk, 45%.

Table 13 Therapeutic options for tumor necrosis factor-α blockers secondary non-response

Continue the same TNFB, but use a higher dose at the same time interval

Continue the same TNFB and the same starting dose, but use a shorter interval between doses

Re-induction therapy with another TNFB

Use another therapeutic option (e.g., tacrolimus or cyclophosphamide)

Surgery

TNFBs: Tumor necrosis factor-α blockers.

Table 14 Therapeutic gain of infliximab for Crohn's disease maintenance of response and remission (%)

Assessment week	Treatment	IFX (mg/kg)			PL	Therapeutic gain
		5	10	20
Remission	0, 2, 6 wk
12		751	-	-	38	371
24		571	-	-	29	281
52		401	-	-	22	181
Response	2, 6, 8 wk
30		501	581	-	27	23-311
54		371	471	-	15	22-321
Remission	2, 6, 8 wk
30		391	39	-	21	181-18
54		281	38	-	14	141-24
Response	q8 wk
54	until week 54	361	-	-	6	301
Response	q8 wk (4 infusions)
36		-	721	-	44	281
44			621	-	37	251
Remission	q8 wk (4 infusions)	-
12		-	141		44	-301
36			601		35	251
44			531		20	331

¹Significant difference. PL: Placebo; IFX: Infliximab.

Table 15 Therapeutic gain of adalimumab maintenance of response and remission (%)

Study	Assessment week	ADA2	ADA3	PL	Therapeutic gain
	Maintenance
CHARM	Response (CDAI ↓≥ 100 pts)
	26	521	521	27	251-251
	56	411	481	17	241-311
	Response (CDAI ↓≥ 70 pts)
	26	541	561	28	261-281
	52	431	491	18	251-311
(Classic II)	Response (CDAI ↓≥ 100 pts)
	24	84	941	61	23-331
	56	79	891	56	23-331
	Remission (CDAI ↓≥ 100 pts)
	26	401	461	17	231-291
	56	361	411	12	241-191
	Remission (CDAI ↓≥ 70 pts)
	24	95	94	83	12-11
	56	79	89	72	7-17
	Remission
	4	95	1001	89	6-111
	12	901	891	56	441-331
	24	841	941	50	341-441
	32	841	1001	39	451-611
	48	74	94	44	30-50
	56	79	83	44	35-39

¹Significant difference;

²40 mg at week 0, 20 mg at week 1;

³80 mg at week 0, 40 mg at week 2. CDAI: Crohn’s disease activity index; PL: Placebo; pts: Points; ADA: Adalimumab; CHARM: Crohn's trial of the fully human antibody adalimumab for remission maintenance.

Table 16 Therapeutic gain of certolizumab Induction of response and remission (%)

Week	Response		TG (CER-PL)
	CER	PL
CRP < 10 mg/L
6	371	26	111
26	22	12	10
Overall population
6	352	27	81
26	232	16	71
Remission
6	17	22	-
6 + 26	10	14	-
Maintenance with CER
Week 26 clinical response	621	34	281
Overall group	631	36	271

¹Significant difference;

²The secondary failure rates for CRP were 72% at 26 wk (approximately 10% per month). Precise I study (Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy I). PL: Placebo; CRP: C-reactive protein; CER: Certolizumab; TG: Therapeutic gain.

Table 17 Therapeutic gain of varying doses of certolizumab

Week	Response				Therapeutic gain
	PL	CER (mg)			CER (mg)
		100	200	400	100	200	400
2	18	33	19	28	15	1	10
4	19	371	26	33	181	7	11
6	18	361	31	391	181	13	211
8	22	36	29	391	14	7	171
10	27	44	36	441	17	9	171
12	23	38	24	391	15	1	161

¹Significant difference. PL: Placebo; CER: Certolizumab.

Table 18 Meta-analysis of efficacy and safety of biological therapies (26 wk to 60 wk) vs placebo in preventing relapse of disease activity in quiescent luminal Crohn's disease

Treatment	Outcome (RR in preventing relapse)
IFX, ADA, CER	RR = 0.71 (95%CI: 0.65-0.76, I2 = 5%, P = 0.38); NNT = 4 (95%CI: 3-5)
IFX, CER	Superior to PL
ADA	No statistically significant difference between ADA vs PL in preventing relapse
NAT (only one trial)	RR = 0.71; 95%CI: 0.61-0.84
Adverse events
Any event	RR = 0.93; 95%CI: 0.84–1.03
Infusion or injection site reactions	RR = 0.64; 95%CI: 0.06-6.66; (note that these reactions were actually fewer in those on anti-TNFα therapy, but the difference was not statistically significant)

PL: Placebo; CER: Certolizumab; IFX: Infliximab; ADA: Adalimumab; TNF: Tumor necrosis factor; RR: Risk ratio; CI: Confidence interval; NAT: Natalizumab.

Table 19 Comparative efficacy of infliximab, adalimumab and certolizumab (%)

Induction	Response1	Remission2		Therapeutic gain
		TNFBs	PL
AccentI	58	39	21	18
CHARM	58	46	17	29
Precise 2	64	48	29	19

¹Weeks 2 to 6;

²Weeks 26 to 30. Remission is often defined by the Crohn's disease activity index, but may also be defined using the Inflammatory Bowel Disease Questionnaire. PL: Placebo; TNFBs: Tumor necrosis factor-α blockers; CHARM: Crohn's trial of the fully human antibody adalimumab for remission maintenance.

Table 20 Concurrent immunosuppression with azathioprine plus infliximab vs azathioprine alone in Crohn’s disease[53] (%)

	Week
	12	24	52
AZA	38	29	22
AZA + IFX x3	751	571	40
Therapeutic gain	371	281	18

¹Significant difference. AZA: Azathioprine; IFX: Infliximab.

Table 21 Infliximab for fistulizing Crohn's disease: Induction and maintenance (%)

Study	Week of assessment	Outcome	IFX (mg/kg)		PL	TG
			5	10
Present et al[75]	18	Response	681	561	26	42-30
		Closure	551	381	13	42-25
(ACCENT II)	54	Response	461		23	23
		Closure	361		19	17

¹Complete closure of draining fistulas; P value for each IFX group vs placebo group. For IFX 5 mg/kg, the TG for fistula closure ranged from 42% at 18 wk to 23% to 54 wk. Adapted from CADTH (’09). These differences are statistically significant. See Tables 3 and 4 of the CADTH report for P-values, number of participants and events. IFX: Infliximab; PL: Placebo; TG: Therapeutic gain.

Table 22 Adalimumab for fistulizing Crohn's disease induction, response and closure (%)

Study	Assessment week	ADA1	ADA2	ADA3	PL	TG
GAIN	Response
	4	-	-	15	20	(-5)
	Closure
	4	-	-	5	8	(-3)
Classic I	Response
	4	75	20	8	33	(42, -13, -25)
	Closure
	4	75	0	0	17	(58, -17, -17)

¹40 mg at week 0, 20 mg at week 2;

²80 mg at week 0, 40 mg at week 2;

³160 mg at week 0, 80 mg at week 2. ADA: Adalimumab; PL: Placebo; TG: Therapeutic gain.

Table 23 Adalimumab for fistulizing Crohn's disease maintenance (%)

Study	Assessment week	Combined ADA group1	PL	TG
CHARM	Closure
	26	30	13	17
	56	33	13	20

¹Statistically significant. Note that the two higher dose regimes of ADA do poorly for induction of fistulizing CD. The TG for IFX and ADA for fistula closure at 54-56 wk is a similar low value of 17%. PL: Placebo; TG: Therapeutic gain; ADA: Adalimumab; CHARM: Crohn's trial of the fully human antibody adalimumab for remission maintenance; IFX: Infliximab; CD: Crohn's disease. 140 mg q0w and 40 mg qw.

Table 24 Meta-analysis of efficacy and safety of biological therapies vs placebo (4 wk to 26 wk) in healing of fistulizing Crohn's disease

Treatment	Outcome (RR of fistulas remaining unhealed)
IFX, ADA, CER vs PL (4 wk to 26 wk)	RR = 0.88; 95%CI: 0.73-1.05; I2 = 67%, P = 0.01 (considerable heterogeneity between studies, with no statistically significant difference in fistula healing at 4 wk to 26 wk, compared to placebo, when considering the 3 TNFB)
IFX vs PL (one trial)	RR = 0.62; 95%CI: 0.48-0.81
IFX, ADA, CER vs PL (excluding 2 trials reporting fistula healing up to only 4 wk)	RR = 0.80; 95%CI: 0.65-0.98; I2 = 56%, P = 0.08 (heterogeneity between studies remained)
IFX (only 1 trial) vs > PL (followed until 54 wk)	RR = 0.81; 95%CI: 0.68-0.96

Adverse events could not be determined from data. CER: Certolizumab; IFX: Infliximab; ADA: Adalimumab; PL: Placebo; RR: Risk ratio; TNFB: TNF-α blockers; CI: Confidence interval.

Table 25 Reduction (%) of health service utilization in Crohn's disease patients treated with Infliximab

	All CD patients[180]	CD fistula patients
		(Rubenstein et al[180])	(Harrison et al[181])
ER visits	66	64	372
All surgery	38	66
GI surgery	18	59
Hospitalizations		59	37
Endoscopies	43		52
Radiographs	12	40	58-147
Outpatient visits	16	27	22-33

CD: Crohn's disease; ER: Emergency Room; GI: Gastrointestinal.

Table 26 Natural history of Crohn’s disease and ulcerative colitis %

Natural history
UC		CD1
Remission at any point in time	50	Relapse	10-30
Overall intermittent course	90	Low activity	15-20
Remission: 3-7 yr after diagnosis	25	Remission	55-65
Yearly relapse	18	Chronic active	13-20
Intermittent relapse	51	Chronic intermittent	67-73
		Remission for 10 yr	13
10 yr colectomy rate	10	Surgery by 20 yr	> 75
Change in site of UC over 25 yr		Change in behavior
LC→ C	50	NSNF → S	27
C → LC	75	NSNF → F	29

¹Course 1 year after diagnosis. C: Entire colon; LC: Left colon; S: Structuring; F: Fistulising; NSNF: Non-stricturing, non-fistulizing; UC: Ulcerative colitis; CD: Crohn's disease.

Table 27 Meta-analysis of efficacy and safety of biological therapies vs placebo in inducing remission in moderately to severely active ulcerative colitis[61]

Treatment	Outcome (RR of remission not being achieved)
IFX vs PL	RR = 0.72; 95%CI: 0.57-0.91
	NNT = 4 (95%CI: 3-8)
Adverse event
Any adverse event was no higher in IFX vs PL, and risk of serious adverse events was lower	RR of serious adverse event = 0.64; 95%CI: 0.41-1.00, P = 0.05
	NNH = 13 (95%CI: 8-50)

IFX: Infliximab; PL: Placebo; RR: Risk ratio; CI: Confidence interval; UC: Ulcerative colitis; NNT: Needed to treat.

Table 28 Associations of mucosal healing in Crohn's disease

Fewer symptoms
No previous surgery
Previous surgery
Less inflammation at 5 yr requiring steroid use
Less use of steroids
Steroid-free remission and no flare at years 3 and 4	Yes (TG, 44%)
Steroid-free remission, no flare and no TNFB at years 3 and 4	Yes (TG, 44%)
No new or persistently active fistulas	No

How do these associations with mucosal healing (MH) in CD compare with UC? About 90% of patients remain asymptomatic after achieving MH on once-a-day 5-aminosalicylic acid (Mezavant^®), and after MH, 40% of UC patients remain asymptomatic (TG, 22%). TG: Therapeutic gain; CD: Crohn's disease; UC: Ulcerative colitis; TNFB: Tumor necrosis factor-α blockers (response in active treatment group minus response in placebo group; differences statistically significant).

Table 29 Rates of therapy-associated mucosal healing

Drug	CD		UC
	Week1	MH, %	Week1	MH, %
5-ASA			4-8	25-71
Prednisone	4-9	0-27
AZA	16-96	40-73	26	53-69
MTX	12-60	36-38
IFX	4-104	29-100	8-52	62-71
ADA	12	27	8	30
CER	10	5-55

¹Time for endoscopic assessment of mucosal healing. CD: Crohn's disease; UC: Ulcerative colitis; MH: Mucosal healing; 5-ASA: 5-Aminosalicylic acid; AZA: Azathioprine; MTX: Methotrexate; IFX: Infliximab; ADA: Adalimumab; CER: Certolizumab.

Table 30 Complete mucosal healing¹

	ADA	PL [ADA induction only (3 doses)]	TG (%)
ITT		PL
week 12	27%	13% (P = 0.056)	14
week 52	24%	0% (P < 0.001)	24
PP
week 12	28%	13% (P = 0.046)	15

¹Extend: Open-label adalimumab[182]. Of patients with CMH at week 12, 46% of ADA every other weeks had CMH at week 52 vs 0% CMH in those receiving only ADA induction. ITT: Intention-to-treat; PP: Per protocol; TG: Therapeutic gain; PL: Placebo; ADA: Adalimumab.

Table 31 Meta-analysis efficacy of 5-aminosalicylic acid/sulfasalazine to induce remission or to prevent relapse in Crohn's disease

	Induce remission (RR of not being in remission) on active therapy	Prevent relapse (RR of relapse)
CD	SASP (only 2 RCTs) 0.83 (95%CI: 0.69-1.00; trend)	SASP/5-ASA, ITT analysis, no benefit
	5-ASA 0.91 (95%CI: 0.77-1.06; not significant)	5-ASA, PP analysis: RR = 0.79 (95%CI: 0.66-0.95; NNT = 13 to prevent relapse)
UC	0.79 (95%CI: 0.73-0.85; NNT = 6)	0.65 (95%CI: 0.55-0.76; NNT = 4 to prevent relapse)

CD: Crohn's disease; ITT: Intention-to-treat; PP: Per protocol; SASP: Sulfasalazine; 5-ASA: 5-Aminosalicylic acid; CI: Confidence interval; UC: Ulcerative colitis; NNT: Needed to treat; RR: Relative risk; RCT: Randomized controlled trial.

Table 32 Efficacy of various antibiotics to induce remission or to prevent relapse in Crohn's disease

		Induce remission (RR of not remission) on active therapy	Prevent relapse (RR of relapse)
CD	Inflammatory disease	0.85 (95%CI: 0.73-0.99, P = 0.03)	0.62 (95%CI: 0.46-0.84)
	Perianal fistula	0.80 (95%CI: 0.66-0.98)
UC		0.64 (95%CI: 0.43-0.96)

UC: Ulcerative colitis; CD: Crohn's disease; CI: Confidence interval; RR: Risk ratio.

Table 33 Meta-analysis of efficacy of immunosuppressive therapy to induce remission or to prevent relapse in Crohn's disease and ulcerative colitis

		Induce remission (RR of not being in remission on active therapy)	Prevent relapse (RR of relapse)
CD	AZA/6-MP vs placebo/no therapy	0.87 (95%CI: 0.71-1.06)	0.64 (95%CI: 0.34-1.23)
		If OR was used rather than RRs as the summary statistic, then “the result was significant, using a random effects model (OR = 0.42; 95%CI: 0.2-0.89)	There was no statistically significant benefit for continuing AZA to prevent CD relapse (RR = 0.39; 95%CI: 0.21-0.74)
	MTX vs placebo	0.82 (95%CI: 0.65-1.03), no statistically significant benefit	IM MTX: 0.57 (95%CI: 0.35-0.94); NNT = 4 (95%CI: 2-25) to prevent one relapse
		If or used, then the result was statistically significant: OR = 0.47; 95%CI: 0.23-0.99	PO MTX to facilitate steroid withdrawal: 0.82 (95%CI: 0.58-1.17)
	Cyclosporine vs placebo (only one trial)	0.84 (95%CI: 0.62-1.07; tacrolimus, one study, no improvement: RR = 0.64; 95%CI: 0.44-0.92)	0.96 (95%CI: 0.77-1.20)
UC	AZA vs placebo	0.85 (95%CI: 0.71-0.01, P = 0.07)	0.60 (95%CI: 0.37-0.95, P = 0.03); NNT = 4, 95%CI: 2-10)
	MTX vs placebo	0.59 (95%CI: 0.04-7.90)

UC: Ulcerative colitis; AZA: Azathioprine; MTX: Methotrexate; RR: Risk ratio; OR: Odds ratio; NNT: Needed to treat; CI: Confidence interval; IM: Intramuscular; PO: Oral; CD: Crohn's disease; 6-MP: 6-mercaptopurine.

Table 34 Benefits of mucosal healing in Crohn's disease[183]

Positive: IBSEN, Step-up/top-down, SONIC

IBSEN (Froslie): 5-yr longitudinal study of IBD patients not on TNFB and enjoying mucosal healing

CD: ↓ Inflammation, ↓ Future use of steroids

UC: ↓ Risk of future colectomy

Negative: Music

IBSEN: The inflammatory bowel south-eastern Norway (study group of gastroenterologists); SONIC: Study of biologic and immunomodulator naive patients in Crohn’s disease; TNFB: Tumor necrosis factor-α blockers; IBD: Inflammatory bowel disease; CD: Crohn's disease; UC: Ulcerative colitis.

Table 35 SONIC (Crohn's disease diagnosed within 4 years) %

Conventional step-up (steroids→AZA→IFX)	Step-down (IFX x3, with AZA)
2 yr	30	73	(43)
3-4 yr
No flare, no steroids, on demand IFX	about 65	about 20	(about 45)
No flare, no steroids, no TNFB	about 60	about 15	(about 45)
New or persistent fistulas	about 2	about 22	(about 20)

IFX: Infliximab; AZA: Azathioprine; TNFB: Tumor necrosis factor-α blockers.

Table 36 Sonic naive (no azathioprine, no tumor necrosis factor-α blockers) %

	Clinical remission, off steroids
	AZA	IFX	AZA + IFX
26 wk	30	44	57
50 wk	24	35	46
	17	30	441

¹AZA + IFX vs IFX (P = 0.55) or vs AZA (P≤ 0.001). IFX: Infliximab; AZA: Azathioprine.

Table 37 Adverse effects for infliximab and adalimumab¹

	IFX	ADA
All AEs	-	-
Serious AEs	-6.6	-4.72
Nausea	+7.93	+2.4
Pharyngitis	+16.1	+3.72
Injection site infection	-	+3.82
Injection site reaction	-	+10.52
Arthralgias	-	+4.32
Urinary tract infections	-	+3.52

¹The rates are shown as the percentage differences in the rates of AEs in tumor necrosis factor-α blocker minus placebo groups. AEs are shown, with the increased (+) or decreased (-) difference from placebo. Note that the duration of follow-up observation varied between study, and has not been standardized here (e.g., per 100 treatment years);

²The statistically significant or trends: (1) Note that the rates of all AEs as well as serious AEs were lower than in the placebo groups; and (2) Serious AEs include lymphoma and other cancers;

³Significant difference. IFX: Infliximab; ADA: Adalimumab; AEs: Adverse effects.

Table 38 Some of the important anti-tumor necrosis factor studies still to be reported

Direct head-to-head comparisons of various anti-TNFs

Further evidence that treating with anti-TNFs earlier after the diagnosis of CD is better

Further clarification of the role of using scheduled anti-TNF therapy without concomitant AZA/MTX

Head-to-head trials comparing the effectiveness of IFX, ADA, and CER peg with conventional therapy in refractory CD (other than newly diagnosed and treatment naive patients)

Long-term safety

Evidence for efficacy of switch from ADA → IFX for ADA secondary loss of response

Optimal therapy for anti-TNF therapy primary non-responders

The comparison of standard-of-care vs anti-TNF therapy for maintenance therapy in UC

Are physicians correctly distinguishing mild from moderate or severe CD?

What is the profile of the patient who is most likely to respond? Are they genotypic or phenotypic characteristics?

When is the optimal time in the course of the patient’s illness to begin anti-TNF therapy?

TNF: Tumor necrosis factor; CD: Crohn's disease; AZA: Azathioprine; MTX: Methotrexate; IFX: Infliximab; ADA: Adalimumab; CER: Certolizumab; UC: Ulcerative colitis.