Key points

Introduction

Tumor necrosis factor-α (TNF) is a key pro-inflammatory cytokine in Crohn disease (CD). Produced mainly by activated macrophages and T lymphocytes, TNF induces many other pro-inflammatory cytokines, including interleukin-1 and interleukin-6, enhances leukocyte migration by inducing expression of adhesion molecules by endothelial cells and leukocytes, activates leukocytes, induces acute phase reactants and metalloproteinases, and inhibits apoptosis of inflammatory cells. Anti-TNF agents, by binding to membrane-bound and soluble TNF, induce destruction of immune cells by antibody-dependent cellular toxicity, induce T-cell apoptosis by binding to membrane-bound TNF, and neutralize the effects of soluble TNF. Currently, anti-TNF agents are the mainstay of treatment for the induction and maintenance of remission in patients with moderate to severe CD.

Three anti-TNF agents have been approved by the US Food and Drug Administration for the management of CD: infliximab (IFX), adalimumab (ADA), and certolizumab pegol (CZP). IFX is a chimeric monoclonal immunoglobulin G1 (IgG1) antibody against TNF composed of 75% human and 25% murine sequences. It is administered intravenously, over 1 to 3 hours, with standard weight-based dosing of 5 mg/kg body weight at weeks 0, 2, and 6 for induction, followed by 5 mg/kg every 8 weeks for maintenance of remission. ADA is a fully human, monoclonal IgG1 antibody against TNF. It is administered subcutaneously with standard dosing of 160 mg and 80 mg at weeks 0 and 2 for induction, followed by 40 mg every 2 weeks for maintenance of remission. CZP contains the Fab fragment of a humanized anti-TNF monoclonal antibody, and to increase plasma half-life, the Fab fragment is covalently attached to a polyethylene glycol moiety, far removed from the antigen-binding site, to prevent interference. Like ADA, it is administered subcutaneously, with standard dosing of 400 mg at weeks 0, 2, and 4 for induction, followed by 400 mg every 4 weeks for maintenance of remission. In this review, the efficacy, predictors of response, primary and secondary nonresponse to anti-TNF therapy, as well as the use of anti-TNF therapy in special situations are discussed. Evidence on optimal use of anti-TNF therapy (step-up vs top-down therapy; withdrawal of anti-TNF therapy), combination immunosuppressive therapy, and therapeutic drug monitoring is discussed elsewhere in this issue.

Introduction

Tumor necrosis factor-α (TNF) is a key pro-inflammatory cytokine in Crohn disease (CD). Produced mainly by activated macrophages and T lymphocytes, TNF induces many other pro-inflammatory cytokines, including interleukin-1 and interleukin-6, enhances leukocyte migration by inducing expression of adhesion molecules by endothelial cells and leukocytes, activates leukocytes, induces acute phase reactants and metalloproteinases, and inhibits apoptosis of inflammatory cells. Anti-TNF agents, by binding to membrane-bound and soluble TNF, induce destruction of immune cells by antibody-dependent cellular toxicity, induce T-cell apoptosis by binding to membrane-bound TNF, and neutralize the effects of soluble TNF. Currently, anti-TNF agents are the mainstay of treatment for the induction and maintenance of remission in patients with moderate to severe CD.

Three anti-TNF agents have been approved by the US Food and Drug Administration for the management of CD: infliximab (IFX), adalimumab (ADA), and certolizumab pegol (CZP). IFX is a chimeric monoclonal immunoglobulin G1 (IgG1) antibody against TNF composed of 75% human and 25% murine sequences. It is administered intravenously, over 1 to 3 hours, with standard weight-based dosing of 5 mg/kg body weight at weeks 0, 2, and 6 for induction, followed by 5 mg/kg every 8 weeks for maintenance of remission. ADA is a fully human, monoclonal IgG1 antibody against TNF. It is administered subcutaneously with standard dosing of 160 mg and 80 mg at weeks 0 and 2 for induction, followed by 40 mg every 2 weeks for maintenance of remission. CZP contains the Fab fragment of a humanized anti-TNF monoclonal antibody, and to increase plasma half-life, the Fab fragment is covalently attached to a polyethylene glycol moiety, far removed from the antigen-binding site, to prevent interference. Like ADA, it is administered subcutaneously, with standard dosing of 400 mg at weeks 0, 2, and 4 for induction, followed by 400 mg every 4 weeks for maintenance of remission. In this review, the efficacy, predictors of response, primary and secondary nonresponse to anti-TNF therapy, as well as the use of anti-TNF therapy in special situations are discussed. Evidence on optimal use of anti-TNF therapy (step-up vs top-down therapy; withdrawal of anti-TNF therapy), combination immunosuppressive therapy, and therapeutic drug monitoring is discussed elsewhere in this issue.

Efficacy of anti-TNF therapy

The goals of therapy in CD are to induce and maintain corticosteroid-free remission, achieve mucosal healing, improve quality of life, reduce the need for surgery and hospitalization, as well as reduce long-term risk of small intestinal and colorectal adenocarcinoma. Anti-TNF therapy is effective in achieving these goals in moderate to severe luminal CD, especially in steroid-dependent patients, patients intolerant to or with progressive disease despite immunomodulator therapy, and for penetrating CD. It also appears to be an effective maintenance therapy in patients at high risk of CD recurrence after surgically induced remission. Currently, a minority of patients are treated with anti-TNF agents based on nationwide administrative database studies, although, with increasing understanding of disease behavior and the potential for disease modification by anti-TNFs, their use is likely to increase.

Clinical Remission

Tables 1 and 2 summarize the key randomized controlled trials (RCTs) of induction and maintenance of remission with anti-TNF therapy in luminal CD. Overall, in RCTs of patients with moderate to severe luminal CD, clinical remission rates at weeks 4 to 12 were 33% to 72% for IFX, 21% to 43% for ADA (36%–43% in anti-TNF-naïve patients, 21%–26% in anti-TNF-exposed patients), and 22% to 32% for CZP (32%–40% in anti-TNF-naïve patients, 24% in anti-TNF-exposed patients). On meta-analysis, remission of CD was achieved in 456/1598 anti-TNF-treated patients (28.5%) at 4 to 12 weeks, compared with 223/1158 placebo-treated patients (19.3%); rates of clinical response were higher. These rates correspond to a 13% lower risk of failure to achieve remission (95% confidence interval [CI], 6%–20%) and 8 patients would need to be treated with IFX to achieve clinical remission in one more patient after induction therapy compared with placebo (number needed to treat [NNT], 8; 95% CI, 6–17). At 10 to 12 weeks, induction therapy with IFX achieved remission in 45.3% of patients (compared with 25.3% of patients treated with placebo); this corresponds to a 32% lower risk of failure to achieve remission (95% CI, 10%–48%) and NNT of 4 (95% CI, 3–7). Likewise, induction therapy with ADA achieved remission in 24.2% of patients (compared with 9.1% of patients treated with placebo); this corresponds to a 15% lower risk of failure to achieve remission (95% CI, 9%–21%) and an NNT of 7 (95% CI, 5–12.5). On the other hand, on meta-analysis of 4 RCTs of CZP induction therapy, remission was achieved in 24.7% of CZP-treated patients and 21% of placebo-treated patients. Induction therapy with CZP was not superior to placebo in achieving remission (relative risk [RR], 0.95; 95% CI, 0.90–1.01). However, it should be noted that there were differences in trial design, especially for CZP, which may account for some of the differences in the observed efficacy of these agents.

Table 1

Key RCT on the efficacy of anti-TNF therapy for induction of remission in luminal CD

Study, Year of Publication	Location, Time Period	Participants	Intervention (and Comparator)	Outcomes of Interest	Key Results
INFLIXIMAB
Targan et al, 1997	North America and Europe, 18 sites; 1995–1996	Luminal, moderate-severe CD (CDAI 220–450); 16% Ileal, 54% ileocolonic, 30% colonic; 108 patients	IFX 5 mg/kg, 10 mg/kg, or 20 mg/kg at week 0; placebo	Remission: CDAI <150, week 4 and 12 Response: 70-point decrease in CDAI, week 4 and 12	1. Remission: IFX (all doses) vs placebo: 33% vs 4% (week 4), 24% vs 8% (week 12) 2. Response: IFX (all doses) vs placebo: 65% vs 16% (week 4), 41% vs 12% (week 12)
Lemann et al, 2006	France, 22 sites; 2000–2002	Luminal moderate-severe CD, all patients with steroid-dependent CD; 20% ileal, 51% ileocolonic, 29% colonic; 115 patients	IFX 5 mg/kg or 10 mg/kg at weeks 0, 2, and 6; placebo (all patients received azathioprine or 6-mercaptopurine)	Remission: CDAI <150 (steroid-free), week 12 and 24	1. Steroid-free remission: IFX (all doses) vs placebo: 72% vs 36% (week 12), 53% vs 26% (week 24)
Colombel et al (SONIC), 2010	Multinational, 92 sites; 2005–2008	Luminal, moderate-severe CD (CDAI 220–450), all patients were immunomodulator-naïve; 36% ileal, 42% ileocolonic, 22% colonic; 508 patients	IFX 5 mg/kg at weeks 0, 2, and 6, and then every 8 wk; azathioprine 2.5 mg/kg/d; IFX + azathioprine (combination)	Remission: CDAI <150 (steroid-free), week 10 Response: 100-point decrease in CDAI, week 10 Mucosal healing: absence of mucosal ulceration at week 26 in patients who had confirmed mucosal ulceration at baseline	1. Steroid-free remission: IFX vs AZA (vs combination): 37% vs 24% (vs 47%) 2. Response: IFX vs AZA (vs combination): 56% vs 39% (vs 69%) 3. Mucosal healing: IFX vs AZA (vs combination): 30% vs 16% (vs 44%)
ADALIMUMAB
Hanauer et al (CLASSIC-I), 2006	Multinational, 55 sites; 2002–2003	Luminal, moderate-severe CD (CDAI 220–450); 62% ileal, 9% ileocolonic, 25% colonic; 299 patients	ADA 40/20 mg, 80/40 mg, or 160/80 mg at weeks 0 and 2; placebo (excluded patients with previous anti-TNF therapy)	Remission: CDAI <150, week 4 Response: 100-point decrease in CDAI, week 4	1. Remission: ADA 160/80 vs placebo: 36% vs 12% 2. Response: ADA 160/80 vs placebo: 50% vs 25%
Sandborn et al (GAIN), 2007	North America and Europe, 52 sites; 2005–2006	Luminal, moderate-severe CD (CDAI 220–450), with prior intolerance to IFX or loss of response; 325 patients	ADA 160/80 mg at weeks 0 and 2; placebo	Remission: CDAI <150, week 4 Response: 100-point decrease in CDAI, week 4	1. Remission: ADA vs placebo: 21% vs 7% 2. Response: ADA vs placebo: 38% vs 25%
Watanabe et al, 2012	Japan, 2007	Luminal, moderate-severe CD (CDAI 220–450); 113 patients	ADA 80/40 mg, or 160/80 mg at weeks 0 and 2; placebo	Remission: CDAI <150, week 4 Response: 100-point decrease in CDAI, week 4; analysis stratified by previous anti-TNF exposure	In anti-TNF exposed patients: 1. Remission: ADA 160/80 vs placebo: 26% vs 8% 2. Response: ADA 160/80 vs placebo: 42% vs 15% In anti-TNF naïve patients: 3. Remission: ADA 160/80 vs placebo: 43% vs 20% 4. Response: ADA 160/80 vs placebo: 50% vs 20%
CERTOLIZUMAB PEGOL
Schreiber et al, 2005	Multinational, 58 centers; 2001–2002	Luminal, moderate-severe CD (CDAI 220–450); 291 patients	CZP 100 mg, 200 mg, or 400 mg at weeks 0, 4, and 8; placebo	Remission: CDAI <150, week 12 Response: 100-point decrease in CDAI, week 12	1. Remission: CZP (all doses) vs placebo: 24% vs 23% 2. Response: CZP (all doses) vs placebo: 39% vs 36%
Sandborn et al (PRECISE 1), 2007	Multinational, 171 centers; 2003–2005	Luminal, moderate-severe CD (CDAI 220–450); 28% ileal, 48% ileocolonic, 24% colonic; 659 patients	Certolizumab 400 mg at weeks 0, 2, and 4; placebo	Remission: CDAI <150, week 6 Response: 100-point decrease in CDAI, week 6; analysis stratified by previous anti-TNF exposure	1. Remission: CZP vs placebo: 22% vs 17% 2. Response: CZP vs placebo: 35% vs 27% In anti-TNF exposed patients: 3. Response: CZP vs placebo: 24% vs 20% In anti-TNF naïve patients: 4. Response: CZP vs placebo: 40% vs 29%
Sandborn et al, 2011	Multinational, 120 sites; 2008–2009	Luminal, moderate-severe CD (CDAI 220–450); 27% ileal, 41% ileocolonic, 29% colonic; 421 patients	Certolizumab 400 mg at weeks 0, 2, and 4; placebo (excluded patients with previous anti-TNF therapy)	Remission: CDAI <150, week 6 Response: 100-point decrease in CDAI, week 6	1. Remission: CZP vs placebo: 32% vs 25% 2. Response: CZP vs placebo: 40% vs 34%

Abbreviation: CDAI, Crohn disease activity index.

Data from Refs.

Table 2

Key RCT on the efficacy of anti-TNF therapy for maintenance of remission in patients with luminal CD

Study, Year of Publication	Location, Time Period	Participants	Intervention (and Comparator)	Outcomes of Interest	Key Results
INFLIXIMAB
Rutgeerts et al, 2004	North America and Europe, 17 sites;	Luminal, moderate-severe CD (CDAI 220–450); 14% ileal, 55% ileocolonic, 31% colonic; 73 patients	Initial response to placebo or single-dose IFX (5, 10, or 20 mg/kg) (CR-70) (nonresponders given IFX 10 mg/kg at week 12), then responders randomized to IFX 10 mg/kg at 8-weekly intervals thereafter; placebo	Relapse: CDAI ≥150, or need for surgery, or escalation of medical therapy, week 44 Maintenance of remission: CDAI <150, week 44	1. Relapse: IFX vs placebo: 51% vs 81% 2. Remission: IFX vs placebo: 49% vs 19%
Hanauer et al (ACCENT-I), 2002	Multinational, 55 sites	Luminal, moderate-severe CD (CDAI 220–400); 22% ileal, 55% ileocolonic, 22% colonic; 335 patients	Initial response to open-label single-dose IFX (5 mg/kg), then responders (CR-70), randomized to IFX 5 mg/kg at week 2 and 6, then 5 mg/kg or 10 mg/kg at 8-weekly intervals thereafter; placebo	Relapse: CDAI ≥150, or need for surgery, or escalation of medical therapy, week 30 Maintenance of remission: CDAI <150, week 30	1. Relapse: IFX vs placebo: 58% vs 79% 2. Remission: IFX vs placebo: 42% vs 21%
ADALIMUMAB
Colombel et al (CHARM), 2007	Multinational, 92 sites; 2003–2005	Luminal and penetrating, moderate-severe CD (CDAI 220–450); 499 patients	Initial open-label ADA 80/40, then randomized (stratified by responder status) at week 4 to ADA 40 mg weekly or 40 mg every other week thereafter; placebo	Relapse: CDAI ≥150, week 56 Maintenance of remission in week 4-responders: CDAI <150, week 56 in patients with 70-point decrease in CDAI at week 4	1. Relapse: ADA vs placebo: 62% vs 88% 2. Remission, in week 4 responders: ADA vs placebo: 38% vs 12%
Sandborn et al (CLASSIC-II), 2007	North America and Europe, 53 sites; 2002–2005	Luminal, moderate-severe CD (CDAI 220–450), enrolled in CLASSIC-I trial: included only patients in remission 4 and 8 wk after 2 induction doses of ADA; 55 patients	Initial ADA or placebo as part of CLASSIC-I, then patients with remission (CDAI <150 at week 4 and after 40 mg open-label at week 8) randomized to ADA 40 mg weekly or 40 mg every other week, thereafter; placebo	Relapse: CDAI ≥150, week 56 Maintenance of remission: CDAI <150, week 56	1. Relapse: ADA vs placebo: 19% vs 56% 2. Remission: ADA vs placebo: 81% vs 44%
CERTOLIZUMAB PEGOL
Schreiber et al (PRECISE 2), 2007	Multinational, 147; 2004–2005	Luminal and penetrating, moderate-severe CD (CDAI 220–450); 428 patients	Initial open-label CZP 400 mg at weeks 0, 2, 4, then patients with response (CR100) at week 6, randomized to CZP 400 mg every 4 wk; placebo	Relapse: CDAI ≥150, week 26 Maintenance of remission: CDAI <150, week 26	1. Relapse: CZP vs placebo: 52% vs 72% 2. Remission: CZP vs placebo: 29% vs 48%

Abbreviation: CDAI, Crohn disease activity index.

Data from Refs.

In RCTs evaluating maintenance of remission after open-label induction, clinical remission rates at weeks 30 to 56 were 42% to 49% for IFX, 38% to 81% for ADA, and 48% for CZP in luminal CD. On pooling data from 5 RCTs of maintenance therapy with anti-TNF, 44.1% of initial responders to induction therapy, who continued on anti-TNF therapy, were able to maintain remission 26 to 60 weeks later; in contrast, only 21.6% of patients treated with placebo were able to maintain remission. The RR of relapse with anti-TNF compared with placebo was 0.71 (95% CI, 0.65–0.76), with the corresponding NNT to prevent one CD patient from relapsing of 4 (95% CI, 3–5). For IFX, ADA, and CZP, the RR of relapse after achieving remission, compared with placebo was 0.72 (95% CI, 0.63–0.83), 0.54 (95% CI, 0.27–1.07), and 0.73 (0.63–0.85), respectively. Steroid-free remission was reported in 12% to 16% of patients at weeks 48 to 52 for IFX and 23% to 29% for ADA.

Similar results have been observed for clinical response (defined as decrease in Crohn Disease Activity Index score by 70 points) to anti-TNF therapy. Patients treated with anti-TNF agents were 64% more likely to achieve clinical response at week 4 after induction therapy than placebo (RR, 1.64; 95% CI, 1.37–1.95); likewise, among patients with initial response to induction therapy, maintenance therapy with anti-TNF agents was twice as likely to maintain clinical response than placebo (RR, 2.06; 95% CI, 1.32–3.23).

Table 3 summarizes the RCTs of fistula healing with anti-TNF therapy. Of note, only IFX has been specifically studied with fistula healing as the primary endpoint in an RCT in patients with penetrating CD ; RCTs of other agents have reported fistula healing as a secondary endpoint in a subset of patients with penetrating disease. In these RCTs, complete fistula closure rates at weeks 18 to 56 were 36% to 46% for IFX, 33% for ADA, and 30% to 54% for CZP ; fistula closure was observed in only 8% to 12% of ADA-treated patients in short-term 4-week induction trials. On meta-analysis, the RR of failing to achieve fistula healing with anti-TNF therapy was 0.80 (95% CI, 0.65–0.98) when short-term trials were excluded. Partial fistula healing rates (at least 50% reduction in the number of draining fistulae) are expectedly higher, with 62% of IFX-treated patients achieving partial response, as compared with 26% of placebo-treated patients.

Table 3

Key RCT on the efficacy of anti-TNF therapy for treatment of enterocutaneous and perianal fistulae in patients with penetrating CD

Study, Year of Publication	Location, Time Period	Participants	Intervention (and Comparator)	Outcomes of Interest	Key Results
INFLIXIMAB
Present et al, 1999	US and Europe, 12 sites; 1996	Penetrating CD, single or multiple draining enterocutaneous or perianal fistulae; 94 patients	IFX 5 mg/kg or 10 mg/kg at weeks 0, 2, and 6; placebo	Fistula remission: absence of any draining fistula at 2 consecutive visits, week 18 Fistula improvement: reduction of number of draining fistulae by ≥50% (fistula response) at 2 consecutive visits, week 18	1. Fistula remission: IFX (all doses) vs placebo: 46% vs 13% 2. Fistula improvement: IFX (all doses) vs placebo: 62% vs 26%
Sands et al (ACCENT-II), 2004	Multinational, 45 sites; 2000–2001	Penetrating CD, single or multiple draining enterocutaneous or perianal fistulae	Initial response to open-label IFX (5 mg/kg, at weeks 0, 2, and 6), then responders (fistula improvement) randomized at week 14 to IFX 40 mg every 8 wk thereafter; placebo	Fistula remission: absence of any draining fistulae, week 54	1. Fistula remission: IFX vs placebo: 36% vs 19%
ADALIMUMAB
Hanauer et al (CLASSIC-I), 2006	Multinational, 55 sites; 2002–2003	Enterocutaneous or perianal fistulae at baseline; 32 patients	ADA 40/20 mg, 80/40 mg, or 160/80 mg at weeks 0 and 2; placebo (excluded patients with previous anti-TNF therapy)	Fistula remission: absence of any draining fistula at 2 consecutive visits, week 4 Fistula improvement: reduction of number of draining fistulae by ≥50% (fistula response) at 2 consecutive visits, week 4	1. Fistula remission: ADA (all doses) vs placebo: 12% vs 17% 2. Fistula improvement: ADA (all doses) vs placebo: 23% vs 33%
Sandborn et al (GAIN), 2007	North America and Europe, 52 sites; 2005–2006	Luminal and penetrating, moderate-severe CD, with enterocutaneous or perianal fistulae at baseline in CD patients with prior intolerance to IFX or loss of response (excluded primary nonresponders to IFX); 45 patients	ADA 160/80 mg at weeks 0 and 2; placebo	Fistula remission: absence of any draining fistula at 2 consecutive visits, week 4 Fistula improvement: reduction of number of draining fistulae by ≥50% (fistula response) at 2 consecutive visits, week 4	1. Fistula remission: ADA vs placebo: 8% vs 5% 2. Fistula improvement: ADA vs placebo: 20% vs 15%
Colombel et al (CHARM), 2007	Multinational, 92 sites; 2003–2005	Luminal and penetrating, moderate-severe CD, with enterocutaneous or perianal fistulae at baseline; 117 patients	Initial response to open-label ADA 80/40, then randomized at week 4 to ADA 40 mg weekly or 40 mg every other week thereafter; placebo	Fistula remission: absence of any draining fistula at 2 consecutive visits, weeks 26 and 56	1. Fistula remission: ADA (all doses) vs placebo: 30% vs 13% (week 26), 33% vs 13% (week 56)
CERTOLIZUMAB PEGOL
Sandborn et al (PRECISE 1), 2007	Multinational, 171 centers; 2003–2005	Luminal and penetrating, moderate-severe CD, with enterocutaneous or perianal fistulae at baseline; 107 patients	Certolizumab 400 mg at weeks 0, 2, and 4, then 400 mg at 4-weekly intervals thereafter; placebo	Fistula remission: absence of any draining fistula at 2 consecutive visits, week 26	1. Fistula remission: CZP vs placebo: 30% vs 31%
Schreiber et al (PRECISE 2), 2007	Multinational, 147 centers; 2004–2005	Luminal and penetrating, moderate-severe CD, with enterocutaneous or perianal fistulae at baseline; 58 patients	Initial response to open-label certolizumab (400 mg at weeks 0, 2, 4), then responders (CR-100) randomized to certolizumab 400 mg at week 8, then 400 mg at 4-weekly intervals thereafter; placebo	Fistula remission: absence of any draining fistulae on gentle compression at any 2 consecutive visits after baseline, week 26	1. Fistula remission: CZP vs placebo: 54% vs 43%

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