Biologic therapies in inflammatory bowel disease.

REVIEW ARTICLE Biologic therapies in inflammatory bowel disease LAWRENCE B. COHEN, RADU M. NANAU, FAUSTINE DELZOR, and MANUELA G. NEUMAN TORONTO, ONTARIO, CANADA

Inflammatory bowel disease, including its 2 entities ulcerative colitis and Crohn’s disease, is a chronic medical condition characterized by the destructive inflammation of the intestinal tract. Biologics represent a class of therapeutics with immune intervention potential. These agents block the proinflammatory cascade that triggers the activation and proliferation of T lymphocytes at the level of the intestine, therefore reestablishing the balance between the pro- and anti-inflammatory messages. All 7 biologics showing clinical benefits in inflammatory bowel disease are monoclonal antibodies. The following systematic review discusses the pharmacokinetics and efficacy of the tumor necrosis factor blockers infliximab, adalimumab, certolizumab pegol, and golimumab. In addition, we describe the a4 integrin inhibitors natalizumab and vedolizumab, which are directed against cell adhesion molecules, as well as the interleukin 12/23 blocker ustekinumab. (Translational Research 2014;:1–24) Abbreviations: ADA ¼ antidrug antibodies; ADM ¼ adalimumab; AUC ¼ area under the curve; CD ¼ Crohn’s disease; CI ¼ confidence interval; Cmax ¼ maximum concentration; Ctrough ¼ trough concentration; CZP ¼ certolizumab pegol; GLM ¼ golimumab; HR ¼ hazard ratio; IBD ¼ inflammatory bowel disease; IFX ¼ infliximab; IP ¼ induction phase; MP ¼ maintenance phase; NTZ ¼ natalizumab; OR ¼ odds ratio; RR ¼ relative risk; t1/2 ¼ half-life; Tmax ¼ time to maximum concentration; TNF ¼ tumor necrosis factor; UC ¼ ulcerative colitis; UTK ¼ ustekinumab; VDZ ¼ vedolizumab

nflammatory bowel disease (IBD) is a medical condition characterized by the intermittent destructive inflammation of the intestinal tract. Ulcerative colitis (UC) affects only the intestinal mucosa, whereas Crohn’s disease (CD) affects all layers of the intestinal wall. CD is characterized histologically by transmural

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inflammation with asymmetrical and discontinuous granulomas, and focal lymphoid hyperplasia leading to fibrosis of the intestinal wall. On the contrary, the histologic picture of UC presents inflammation limited to the intestinal mucosa with proportioned continuous crypt abscesses and polymorphonuclear leukocyte

From the Division of Gastroenterology, Sunnybrook Health Science Centre, Toronto, Ontario, Canada; Department of Internal Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada. Conflicts of Interest: All authors have read the journal’s policy on conflicts of interest and have none to declare.

Submitted for publication October 19, 2013; revision submitted November 26, 2013; accepted for publication January 2, 2014.

The authors’ work was funded by In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada.

Reprint requests: Manuela G. Neuman, PhD, Department of Pharmacology and Toxicology, In Vitro Drug Safety and Biotechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario, Canada, M5G 1L7; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.01.002

All authors contributed to the paper.

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infiltration. Genetic predispositions and immune dysregulation causing continued activation of T lymphocytes are the cornerstones of IBD etiology. Moreover, epigenetic and environmental factors, as well as standard practical therapeutic interventions, also play a role in the development and pathogenesis of IBD.1-3 Biologics represent a class of therapeutic agents with immune intervention potential that block the proinflammatory cascade that triggers the activation and proliferation of T lymphocytes at the level of the intestine, therefore reestablishing the balance between the proand anti-inflammatory messages. Biologics used in IBD are monoclonal antibodies. The discovery of biologic therapies follows the understanding of the mechanisms that have been postulated for the pathogenesis of IBD (Fig 1). Noxae (eg, bacterial overgrowth, endotoxins, reactive oxygen species, allergens) activate an inflammatory cascade that leads to the release of proinflammatory cytokines such as tumor necrosis factor (TNF)-a, interferon or interleukin 12/23), all of which ultimately result in inflammation of the intestinal mucosa. As anti-TNF medication, infliximab (IFX; Remicade), adalimumab (ADM; Humira), certolizumab pegol (CZP; Cimzia) and golimumab (GLM; Simponi) are TNF blockers, whereas ustekinumab (UTK; Stelara) is an interleukin 12/23 blocker. Moreover, leukocytes from circulation enter into stromal tissues during the inflammatory cascade. This process involves several steps, including activation of leukocytes that contain selectins, and their ligands (P and E) on endothelial cells. This is followed by the interaction between integrins on the surface of the leukocyte and their ligands on the endothelium, a process that permits leukocytes to adhere and enter the mucosa. Integrins consist of a heterodimer (a and b chains).4 The a4b7 integrinexpressing leukocytes adhere to endothelial surfaces on activation. Natalizumab (NTZ; Tysabri) and vedolizumab (VDZ; formerly MLN0002) target the a4 integrin on T lymphocytes. Both NTZ and VDZ act on the activation, adhesion, and migration of leukocytes into the gut mucosa. NTZ prevents leukocyte migration by targeting both the a4b1 and a4b7 integrins. VDZ targets the integrin selectively, resulting in the inhibition of a4b7/mucosal addressin cellular adhesion molecule 1, without affecting the ability of a4b1/vascular cellular adhesion molecule 1 to function.5 The current systematic review discusses the pharmacokinetics, efficacy, and immunogenicity of these 7 biologics as assessed in clinical trials and clinical practice. MATERIALS AND METHODS

The efficacy of each biologic agent used in IBD was determined from placebo-controlled trials. A PubMed

search was performed using ‘‘infliximab,’’ ‘‘adalimumab,’’ ‘‘certolizumab pegol,’’ ‘‘natalizumab,’’ ‘‘ustekinumab,’’ ‘‘golimumab,’’ and ‘‘vedolizumab,’’ and ‘‘Crohn’s disease,’’ ‘‘ulcerative colitis,’’ and ‘‘inflammatory bowel disease,’’ and the term ‘‘clinical trial.’’ Results from recent open-label studies and clinical practice assessing the efficacy of these drugs (2010 to present) is also included to compare the cohorts chosen for certain traits in clinical trials with nondiscriminant real-world samples. This was accompanied further by a Google Scholar search. TREATMENT REGIMENS

The recommended treatment regimens for biologics used in IBD are summarized in Table I.6-13 Biologics are generally administered in 2 phases: an induction phase (IP) associated with more frequent and generally higher doses meant to initiate clinical improvement, and a maintenance phase (MP) associated with less frequent dosing meant to sustain any response achieved during IP. PHARMACOKINETICS OF BIOLOGICS

Pharmacokinetic data are summarized in the product information of each drug, in the clinical trials detailed in Tables II,12,14-34 III,11,35-41 and IV,33,42-61 as well as in other reports concerned with this type of analysis. Infliximab. The pharmacokinetic profile of IFX shows a linear relationship between the dose administered and the maximum concentration (Cmax). IFX pharmacokinetics are similar between adult and pediatric patients with CD or UC for the same dose.6 Serum levels are associated with the dose given during IP, and with the time interval between doses during MP. The median serum concentration 2 weeks after the previous IFX dose was 17.6 mg/mL (range, 0–48 mg/mL) in a pediatric IBD sample during IP, whereas it was 3.55 mg/mL (range, 0–40 mg/mL) with a median interval between infusions of 6.6 weeks during MP.62 The IFX distribution half-life (t1/2) was 4.3 days, whereas its elimination t1/2 was 18.5 days. Overall, the terminal t1/2 was calculated between 7.7 and 9.5 days.6,63 Adalimumab. The Cmax for ADM was 4.7 6 1.6 mg/ mL in healthy volunteers administered a 40-mg dose. The time to achieve Cmax (Tmax) was 5.5 6 2.3 days.7 The pharmacokinetic profile of ADM is linear between doses of 0.5–10.0 mg/kg administered as a single intravenous infusion.7 Thus, mean serum ADM concentrations at week 4 in a CD sample were proportional to the induction dose administered, and evaluated at 2.79 6 1.48 mg/mL in ADM 40 mg/ 20 mg, 5.65 6 3.06 mg/mL in ADM 80 mg/40 mg,

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Fig 1. Intestinal cells that come under stress from noxae (eg, bacterial overgrowth, endotoxin, reactive oxygen species, allergen) are damaged via an inflammatory cascade. This dynamic inflammation involves the release of proinflammatory cytokines and chemokines that perpetuate the inflammation and permit the activation of leukocytes. The adhesion and migration of leukocytes is helped by the a4b1 and a4b7 integrins. Integrins function as a molecular scaffold for extracellular and intracellular proteins. They are linked further to their receptors, the cellular adhesion molecules. Biologic therapies target either the proinflammatory cytokines (tumor necrosis factor-a [TNF-a] and interleukin-12/23) and block their production, or they target the integrins and block the adhesion of leukocytes to the cells. T cells are CD11 and CD18. ICAM, intercellular adhesion molecule; IFN, interferon; Mph, macrophage; NK, natural killer cell.

and 12.61 6 5.25 mg/mL in ADM 160 mg/80 mg.17,19,22 Mean serum ADM concentrations remained relatively constant through week 52.22 ADM was administered as a high 160-mg/80-mg induction dose in individuals weighing 40 kg or more, and as a low 80/40-mg induction dose in individuals weighing less than 40 kg in a pediatric CD population. Maintenance treatment was also weight based, defined as high dose (40 mg or 20 mg) or low dose (20 mg or 10 mg). These regimens led to a mean ADM concentration at week 26 of 10.4 6 4.26 mg/ mL for the high dose and 3.63 6 2.50 mg/mL for the low dose; and at week 52, 9.48 6 5.61 mg/mL for the high dose and 3.51 6 2.21 mg/mL for the low dose.50 Certolizumab pegol. CZP shows linear pharmacokinetics in healthy volunteers and in patients with CD for doses less than 800 mg administered subcutaneously and less than 10 mg/kg administered intravenously.8 The Cmax measured 2 weeks after the last CZP 400-mg dose was 19.6 mg/mL.25 Its elimination t1/2 is estimated at 14 days.8,64 The Cmax after 52 weeks of CZP treatment was 6.8–7.0 mg/mL, regardless of treatment or serum drug concentration at study entry.26 In addition, CZP crosses the placental barrier only minimally compared with IFX and ADM.8

Golimumab. Pharmacokinetic parameters are available for GLM in healthy Chinese, Japanese, and white males after a single dose of 50 mg or 100 mg,65,66 as well as in patients with UC who received a 200-mg/ 100-mg or 100-mg/50-mg GLM induction and 50 mg or 100 mg GLM maintenance every 4 weeks.38,39 In healthy volunteers, mean Cmax after a 50-mg infusion was 3.6 6 1.6 mg/mL in Chinese men, 2.8 mg/mL in Japanese men, and 2.5 mg/mL in white men. After a 100-mg infusion, mean Cmax was 7.5 6 1.4 mg/mL in Chinese men, 6.7 mg/mL in Japanese men, and 7.2 mg/ mL in white men. Tmax occurred between 4 days and 6 days, whereas the mean terminal t1/2 was 10.8– 11.9 days in Chinese men, 11.9–12.6 days in Japanese men, and 11.1–13.3 days in white men.9,65,66 The mean area under the curve (AUC)N after a 50-mg infusion was 59.8 6 19.8 mg/d/mL in Chinese men, 53.3 mg/d/ mL in Japanese men; and 47.7 mg/d/mL for white men. After a 100-mg infusion, the mean AUC was 132.8 6 27.0 mg/d/mL in Chinese men, 121.6 mg/d/mL in Japanese men, and 129.7 mg/d/mL in white men.65,66 GLM serum levels were dose proportional through week 6 during induction, and a steady state was achieved within 8 weeks of the first MP dose in patients with UC.9,38 The peak serum GLM concentration at week 2 was 6.3 6 3.37 mg/mL in a 200-mg/100-mg dosing regimen and was 11.2 6 5.34 mg/mL in a 400-

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Table I. Recommended treatment regimens for biologics used in irritable bowel disease Dosing regimen Drug

Induction phase

Maintenance phase

Infliximab6

CD and UC: 5 mg/kg IV at wk 0, 2, and 6 Pediatric CD: 5 mg/kg IV at wk 0, 2, and 6 in individuals $6 y

Adalimumab7

CD and UC: 160 mg SC at d 1 and 80 mg at d 15

Certolizumab pegol8 Golimumab9 Natalizumab10

CD and UC: 400 mg SC at wk 0, 2, and 4 UC: 200 mg SC at wk 0 and 100 mg SC at wk 2 CD: 300 mg IV every 4 wk

Vedolizumab11,12 Ustekinumab13

CD and UC: 300 mg IV at wk 0 and wk 4 CD: 45 mg SC at wk 0 and wk 5 for individuals weighing ,100 kg CD: 90 mg SC at wk 0 and wk 5 for individuals weighing $100 kg

CD and UC: 5 mg/kg IV every 8 wk thereafter Infliximab generally not continued in patients with CD with no response by wk 14 Pediatric CD: 5 mg/kg every 8 wk thereafter in individuals $6 y CD and UC: 40 mg SC every 2 wk thereafter Adalimumab continued only in individuals with evidence of clinical remission by wk 8 CD: 400 mg SC every 4 wk thereafter UC: 100 mg SC every 4 wk thereafter CD: 300 mg IV every 4 wk Natalizumab generally not continued in patients with CD with no therapeutic benefit by wk 12 CD and UC: 300 mg IV every 8 wk thereafter CD: 45 mg SC every 12 wk thereafter for individuals weighing ,100 kg CD: 90 mg SC every 12 wk thereafter for individuals weighing $100 kg

Abbreviations: CD, Crohn’s disease; IFX, infliximab; IV, intravenous; SC, subcutaneous; UC, ulcerative colitis.

mg/200-mg dosing regimen.38 The median serum GLM concentration at week 6 was 2.4 6 1.87 mg/mL in the 200-mg/100-mg dosing regimen and was 4.5 6 2.89 mg/mL in the 400-mg/200-mg dosing regimen.38 From weeks 8–54, serum concentrations were approximately double with GLM 100 mg compared with GLM 50 mg every 4 weeks.39 The median serum GLM concentration at week 32 was 1.73 mg/mL with GLM 50 mg every 4 weeks and 3.81 mg/mL with GLM 100 mg every 4 weeks, and 1.81 mg/mL and 3.52 mg/mL, respectively, at week 54.39 Patient weight has no significant effect on GLM clearance in patients with UC.9 Natalizumab. The mean Cmax was 101 6 34 mg/mL in patients with IBD treated with NTZ 300 mg.10 One hour after an NTZ 3-mg/kg infusion, the mean Cmax was 52.8 mg/mL in a small study (average sample weight, 66.4 kg).27 The mean t1/2, volume of distribution, and clearance of NTZ were 10 6 7 days, 5.2 6 2.8 L, and 22 6 22 mL/h, respectively.10 Serum NTZ was detectable for up to 4 weeks after infusion, at which point the mean value was 0.99 mg/mL.27 Vedolizumab. The pharmacokinetics of VDZ were assessed during IP and MP in patients with UC, on days 1 and 85. The serum VDZ concentration increased with increasing dose.41 On day 1, Cmax was 12.5 6 2.5 mg/mL for 0.5 mg/kg, 54.0 6 8.9 mg/mL for 2 mg/kg, 154.3 6 41.5 mg/mL for 6 mg/kg, and 279.0 6 167.9 mg/mL for 10 mg/kg, whereas Cmax was 60.4 6 12.5 mg/mL for 2 mg/kg, 191.9 6 42.6 mg/mL for 6 mg/kg, and

291.9 6 95.0 mg/mL for 10 mg/kg on day 85.32,40,41 The mean t1/2 was 9 days, 15.1 days, 22.0 days, and 20.6 days for the 4 doses, respectively. The AUC was measured at both time points as well. AUCday 0–14 was 375 6 59 mg/d/mL for 2 mg/kg, 1058 6 270 mg/d/mL for 6 mg/kg, and 1765 6 822 mg/d/mL for 10 mg/kg, whereas AUCday 85–99 was 473 6 92 mg/d/mL, 1532 6 227 mg/d/mL, and 2608 6 795 mg/d/mL, respectively.40,41 When VDZ doses of 300 mg were used, treatment every 4 weeks led to mean steadystate concentrations of 38.3 6 24.4 mg/mL and 34.8 6 22.6 mg/mL in UC and CD samples, respectively, whereas mean steady-state concentrations when treatment was administered every 8 weeks were 11.2 6 7.2 mg/mL and 13.0 6 9.1 mg/mL, respectively.11,12 Ustekinumab. UTK pharmacokinetics were measured in healthy Chinese and non-Chinese males after a single subcutaneous dose of 45 mg or 90 mg.67 The mean Cmax was 14.9 6 4.9 mg/mL in non-Chinese males and 16.4 6 4.0 mg/mL in Chinese males after a 90-mg dose, and was 7.6 6 1.8 mg/mL after a 45-mg dose in Chinese males. The average Tmax was 8.5 days in healthy volunteers after a 90-mg dose.13,67 Median t1/2 for the 90-mg dose was 22.4 6 7.0 days in nonChinese males and 21.7 6 4.5 days in Chinese males, and 21.4 6 4.2 days after a 45-mg dose in Chinese healthy volunteers receiving UTK. The mean AUCN after a 90-mg dose was 510 6 123 mg/d/mL in nonChinese males and 510 6 105 mg/d/mL in Chinese males, and was 261 6 53 mg/d/mL after a 45-mg dose

Clinical trial* and patient characteristics ACCENT I, Hanauer et al14 Active CD IFX-naive

ACCENT II, Sands et al15 CD with $1 draining abdominal or perianal fistulas of $3 mo duration

REACH, Hyams et al16 Randomized, open-label trial Moderate to severe pediatric CD CLASSIC I, Hanauer et al17 Moderate to severe CD Naive to other antitumor necrosis factor treatment

Treatment regimens IV induction with IFX 5 mg/ kg at wk 0 R1: IV IFX 5 mg/kg at wk 2 and wk 6, and every 8 wk thereafter until wk 46 R2: IV IFX 5 mg/kg at wk 2 and wk 6, and 10 mg/kg every 8 wk thereafter until wk 46 R3: IV placebo at wk 2 and wk 6, and every 8 wk thereafter until wk 46 IV induction with IFX 5 mg/ kg at wk 0, 2, and 6 Randomized at wk 14 to IV IFX 5 mg/kg or placebo every 8 wk until wk 46

Enhanced response, % in drug group vs % in placebo

Remission, % in drug group vs % in placebo

ADAs

Longer time to loss of response in IFX vs placebo (P 5 0.0002)

Data not given

39% in R1, 45% in R2, and 21% in placebo (OR, 2.7; 95% CI, 1.6–4.6 for IFX overall) at wk 30; similar at wk 50 Sustained remission: 25% in R1, 33% in R2, and 11% in placebo between wk 14 and wk 54

14% positive by wk 54 46% inconclusive†

Longer time to loss of response in IFX maintenance (.40%) vs placebo (14%) (P 5 0.0002) Absence of draining fistulas greater in IFX maintenance (36%) vs placebo (19%) at wk 54 (P 5 0.009) IP: 88% at wk 10

Data not given

Data not given

32% positive 31% negative 29% inconclusive

Data not given

IP: 59% at wk 10

3% positive by wk 54 20% negative 77% inconclusive

MP: 64% in R1 and 33% in R2 (P 5 0.002) at wk 54 54% in R1 (P , 0.05 vs placebo), 59% in R2 (P 5 0.01 vs placebo), 59% in R3 (P 5 0.007 vs placebo), and 37% in placebo at wk 4

MP: 56% in R1 vs 24% in R2 (P , 0.001) at wk 54

34% in R1, 40% in R2, 50% in R3 (P 5 0.001 vs placebo), and 25% in placebo at wk 4

18% in R1, 24% in R2, 36% in R3 (P 5 0.002 vs placebo), and 12% in placebo at wk 4

1 patient positive in placebo at wk 0 1 patient positive in R3 at wk 2 but negative at wk 4

(Continued)

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IV induction with IFX 5 mg/ kg at wk 0, 2, and 6 Randomized at wk 10: R1, IFX every 8 wk until wk 46; R2, IFX every 12 wk until wk 46 SC induction at wk 0 and wk 2 R1: ADM 40 mg, then 20 mg R2: ADM 80 mg, then 40 mg R3: ADM 160 mg, then 80 mg R4: placebo

Response, % in drug group vs % in placebo


Table II. Efficacy of biologics in placebo-controlled trials in CD

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CLASSIC II, Sandborn et al18 Moderate to severe CD (patients from CLASSIC I)

Sandborn et al19 Moderate to severe CD Loss of response or intolerance to IFX Colombel et al20 Moderate to severe CD

Treatment regimens Randomized sample: remission at the end of CLASSIC I, treated for 56 wk R1: 40 mg ADM/wk R2: 40 mg ADM every 2 wk R3: placebo Open-label sample: no remission at the end of CLASSIC I, ADM 40 mg every 2 wk for 56 wk

SC placebo or ADM 160 mg at wk 0 and 80 mg at wk 2 SC induction with 80 mg ADM at wk 0 and 40 mg at wk 2 R1: 40 mg ADM/wk R2: 40 mg ADM every 2 wk R3: placebo



Randomized sample: 89% in R1, 79% in R2, and 72% in placebo (NS; small sample) at wk 56

Randomized sample: 89% in R1, 79% in R2, and 56% in placebo (NS; small sample) at wk 56

Randomized sample: mean change in CDAI –198 in R1, –151 in R2, and –120 for placebo (all, P , 0.05) between baseline and wk 56 Open label: mean response rate 72% at wk 56 Open-label sample: mean change in CDAI –158 between baseline and wk 56 52% vs 34% in placebo (P value not given) at wk 4

Open-label sample: mean enhanced response rate 65% at wk 56

56% in R1, 54% in R2, and 28% in placebo (all, P , 0.001) at wk 26 49% in R1, 43% in R2, and 18% in placebo (P , 0.001 for all) at wk 56 Fistula closure: 30% in R1 1 R2 vs 13% in placebo (P 5 0.043) at wk 26

ADAs

Randomized sample: 83% in R1, 79% in R2, and 44% in placebo (P , 0.05 for all) at wk 56 Open-label sample: mean remission rate 47% at wk 56

2.6% positive by wk 54

38% vs 25% in placebo (P value not given) at wk 4

21% vs 7% in placebo (P , 0.001) at wk 4

100% negative or inconclusive by wk 4

52% in R1, 52% in R2, and 26% in placebo (P , 0.001 for all) at wk 26 48% in R1, 41% in R2, and 16% in placebo (all, P , 0.001) at wk 56

47% in R1, 40% in R2, and 17% in placebo (all, P , 0.001) at wk 26 41% in R1, 36% in R2, and 12% in placebo (all, P , 0.001) at wk 56 Sustained remission: 81% in R1 1 R2 vs 48% in placebo (P value note given) between wk 26 and wk 56 Median time in remission: 392 d in R1 (P , 0.001 vs placebo), 378 d R2 (P 5 0.002 vs placebo), and 127 d in placebo

Not evaluated


Fistula closure: 33% in R1 1 R2 vs 13% in placebo (P 5 0.016) at wk 56


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Clinical trial* and patient characteristics

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Table II (Continued )

Watanabe et al22 Moderate to severe CD

PRECISE 1, Sandborn et al23 Moderate to severe CD

PRECISE 2, Schreiber et al24 Moderate to severe CD

SC induction with 160 mg ADM at wk 0 and 80 mg at wk 2 Randomized at wk 4 to placebo or ADM 40 mg every 2 wk until wk 52 Open-label ADM in patients with flares or no response SC induction at wk 0 and wk 2 R1: 160 mg ADM/80 mg ADM R2: 80 mg ADM/40 mg ADM R3: placebo Maintenance with ADM 40 mg or placebo every 2 wk SC placebo or CZP 400 mg at wk 0, 2, and 4, and every 4 wk thereafter until wk 24

Mucosal healing: 27% vs 13% in placebo (P 5 0.056) at wk 12 Mucosal healing: 24% vs 0% in placebo (P , 0.001) at wk 52

Data not given

Data not given

Not evaluated

70% in R1 (P 5 0.0062 vs placebo), 59% in R2 (NS vs placebo), and 30% in placebo at wk 4

46% in R1, 50% in R2, and 17% in placebo (P , 0.05 for all) at wk 4

33% in R1, 18% in R2, and 13% in placebo (P value note given) at wk 4

6% positive by wk 54

Superior in ADM vs placebo (P , 0.05) at wk 52

Superior in ADM vs placebo (P , 0.05) at wk 52

37% vs 26% in placebo among patients with CRP levels .10 mg/L (P 5 0.04) at wk 6 35% vs 27% in placebo in the overall population (P 5 0.02) at wk 6 Sustained response: 22% vs 12% in placebo among patients with CRP levels .10 mg/L (P 5 0.05) at wk 6 and wk 26 Sustained response: 23% vs 16% in placebo in the overall population (P 5 0.02) wk 6 and wk26 62% vs 34% in placebo among patients with CRP levels .10 mg/L (P , 0.001) at wk 26 63% vs 36% in placebo in the overall population (P , 0.001) at wk 26

Only significant at wk 4 and wk 26


42% vs 26% in placebo among patients with CRP levels .10 mg/L (P 5 0.01) at wk 26 48% vs 29% in placebo in the overall population (P , 0.001) at wk 26


Superior in ADM vs placebo (P , 0.01) at wk 52 46% vs 38% in placebo in the overall population (NS) at wk 6

Data not given

(Continued)

Cohen et al

PRECISE 1 patients with response at wk 6 randomized to SC placebo or CZP 400 mg every 4 wk until wk 24


EXTEND, Rutgeerts et al21 Moderate to severe ileocolonic CD

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PRECISE 3, Lichtenstein et al25 Open-label extension trial Moderate to severe CD Patients who completed PRECISE 2 received open-label CZP 400 mg every 4 wk

Treatment regimens CG, CZP during PRECISE 2

Response, % in drug group vs % in placebo Data not given

DIG, placebo during PRECISE 2



56% in CG vs 38% in DIG (P value not given) at wk 26

48% in CG vs 32% in DIG at wk 26 (P value not given)

Response rates and sustained response rates similar between CG and DIG at wk 52 and wk 80 among patients with response at wk 26

41% in CG vs 30% in DIG at wk 52 (P value not given) 36% in CG vs 23% in DIG at wk 80 (P value not given) Remission rates similar, and sustained remission rates slightly superior in CG vs DIG at wk 52 and wk 80 among patients with response at wk 26 29% in CG vs 44% in DIG at wk 4

ADAs 8% positive in CG at wk 28

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17.7% positive in DIG at wk 28

PRECISE 4, Sandborn et al26 Open-label extension trial Moderate to severe CD Patients with initial response at wk 6 of PRECISE 2 who relapsed by wk 26 of PRECISE 2 Relapse: CDAI increase $70 pt above baseline (PRECISE 2, wk 6) or CDAI $350 pt and greater than baseline (PRECISE 2, wk 6) Gordon et al27 Active CD (CDAI .220 and #450)

SC CZP 400 mg at wk 0, 2, and 4, and every 4 wk thereafter CG, CZP during PRECISE 2 DIG, placebo during PRECISE 2

63% in CG vs 65% DIG at wk 4 41% in CG vs 37% in DIG at wk 52 Sustained response at wk 4 and wk 52: 55% in CG vs 59% DIG

Data not given

IV placebo or NTZ 3 mg/kg

Data not given

39% vs 8% in placebo (NS) at wk 2

11% transiently positive by wk 12

Ghosh et al28 Moderate to severe CD

IV infusions wk 0 and wk 4 R1: NTZ 3 mg/kg, then placebo R2: NTZ 3 mg/kg twice R3: NTZ 6 mg/kg twice R4: placebo twice

Mean CDAI in NTZ: 258 at baseline vs 213 at wk 2 (P 5 0.02) Mean CDAI change NS in placebo at wk 2 59% in R1 (P 5 0.022 vs placebo), 71% in R2 (P , 0.001 vs placebo), 57% in R3 (P 5 0.039 vs placebo), and 38% in placebo at wk 6

Data not given

29% in R1 (NS vs placebo), 44% in R2 (P 5 0.03 vs placebo), 31% in R3 (NS vs placebo), and 27% in placebo at wk 6

7% positive at wk 12

Data not given

35% in CG vs 36% in DIG at wk 52 Sustained remission: 64% in CG vs 54% in DIG at wk 4 and wk 52


IV placebo or NTZ 300 mg at wk 0, 4, and 8

56% vs 49% in placebo (P 5 0.05) at wk 10

Data not given

37% vs 30% in placebo (NS) at wk 10

8.6% positive at any time point

Patients with response in ENACT-1 randomized further to IV placebo or NTZ 300 mg every 4 wk until wk 56

Data not given

IV placebo or NTZ 300 mg at wk 0, 4, and 8

Sustained remission: 44% vs 36% (P 5 0.003) at wk 36 Significant differences in remission at all points between wk 20 and wk 60 Medium time to loss of remission: 137 d vs 59 d in placebo (P , 0.001) 24% vs 16% in placebo (P 5 0.009) at wk 4 38% vs 25% in placebo (P 5 0.001) at wk 12 Sustained remission: 26% vs 16% in placebo (P 5 0.002) at wk 8 and wk 12

Data not given

ENCORE, Targan et al30 Moderate to severe CD Active inflammation (CRP .2.87 mg/L)

Sands et al31 Moderate to severe CD

IV placebo or NTZ 300 mg at wk 0, 4, and 8, with concomitant IFX

Sustained response: 61% vs 28% in placebo (P , 0.001) at wk 36 Significant differences in response at all points between wk 20 and wk 60 Medium time to loss of response: 336 d vs 86 d in placebo (P , 0.001) 51% vs 37% in placebo (P 5 0.001) at wk 4 60% vs 44% in placebo (P , 0.001) at wk 12 Sustained response: 48% vs 32% in placebo (P , 0.001) at wk 8 and 12 Mean CDAI change: 2117.9 vs 268.3 in placebo at wk 4 Significant differences in mean CDAI decreases at wk 4, 8, and 12 (all, P , 0.001) Mean CDAI change: 237.7 vs 13.5 in placebo (P 5 0.084) at wk 6

Data not given

Remission at any point: 46% vs 41% placebo (P value not given)

Feagan et al32 Moderate to severe CD

IV infusions d 1 and d 29 R1: VDZ 0.5 mg/kg

43% in R1, 47% in R2, and 31% in placebo (all, P , 0.05) at wk 8 32% in R1, 43% in R2 (P 5 0.05 vs placebo), and 27% in placebo at wk 16

30% in R1, 37% in R2 (P 5 0.04 vs placebo), and 21% in placebo at wk 8

4% positive for NTZ ADAs by wk 10 13% positive for IFX ADAs by wk 10 n/a

31% vs 26% in placebo (NS) at wk 6 44% in R1 (P 5 0.01 vs placebo), 46% in R2 (P 5 0.005 vs placebo), and 30% in placebo at wk 52

14% vs 7% in placebo (P 5 0.02) at wk 6 39% in R1 (P , 0.001 vs placebo), 36% in R2 (P 5 0.004 vs placebo), and 22% in placebo at wk 52

R2: VDZ 2.0 mg/kg R3: placebo

IV induction with placebo or VDZ 300 mg at wk 0 and wk 2 Maintenance in patients with response at wk 6 R1: VDZ every 8 wk R2: VDZ every 4 wk R3: placebo every 4 wk


4.1% positive at any point through wk 52 0.4% persistently positive ($2 consecutive pt) through wk 52

9

(Continued)

Cohen et al

GEMINI 2, Sandborn et al12 Moderate to severe CD

49% in R1, 53% in R2, and 41% in placebo (NS) at wk 8 Mean reduction in CDAI from baseline: 112 in R1, 135 in R2 (P , 0.05 vs placebo), and 88 in placebo at wk 8 Data not given

9% vs 27% in placebo (P 5 0.004) at wk 4 Sustained enhanced response: 39% vs 22% in placebo (P , 0.001) at wk 8 and wk 12


ENACT-1, Sandborn et al29 Moderate to severe CD ENACT-2, Sandborn et al29 Moderate to severe CD Response to NTZ (CDAI #220 at wk 12)

Sandborn et al33 Double-blind, cross-over trial Moderate to severe CD

CERTIFI, Sandborn et al34 Moderate to severe CD Resistance to 1 of IFX, ADM, or CZP

Treatment regimens R1: SC placebo at wk 0, 1, 2, and 3; then UTK 90 mg at wk 8, 9, 10, and 11 R2: SC UTK 90 mg at wk 0, 1, 2 and 3; then placebo at wk 8, 9, 10, and 11 R3: IV placebo at wk 0, then UTK 4.5 mg/kg at wk 8 R4: IV UTK 4.5 mg/kg at wk 0, then placebo at wk 8 IV induction with placebo or UTK 1, 3, or 6 mg/kg SC maintenance with placebo or UTK 60 mg at wk 8 and wk 16 in patients with response at wk 6




53% in combined UTK vs 30% in combined placebo (P 5 0.02) at wk 4 53% in combined UTK vs 30% in combined placebo (P 5 0.019) at wk 6 49% in combined UTK vs 40% in combined placebo (NS) at wk 8

43% in combined UTK vs 26% in combined placebo (P 5 0.076) at wk 4 49% in combined UTK vs 25% in combined placebo (P 5 0.010) at wk 6 49% in combined UTK vs 30% in combined placebo (P 5 0.052) at wk 8

22% in combined UTK vs 9% in combined placebo (NS) at wk 2 26% in combined UTK vs 15% in combined placebo (NS) at wk 4 26% in combined UTK vs 17% in combined placebo (NS) at wk 6 and wk 8

0% positive by wk 54 24% undetectable by wk 54 76% negative by wk 54

Higher in UTK at all doses vs placebo at wk 2, 4, and 6 Decrease in CDAI greater in UTK at all doses vs placebo at wk 2, 4, and 6 No differences in mucosal healing rates

40% in 6 mg/kg (P 5 0.005 vs placebo), 34% in 3 mg/kg (P 5 0.06 vs placebo), 37% in 1 mg/kg (P 5 0.02 vs placebo), and 24% in placebo at wk 6; 69% vs 42% in placebo (P , 0.001) at wk 22

12% in 6 mg/kg, 16% in 3 mg/kg, 16% in 1 mg/kg, 11% placebo (NS for all) at wk 6 42% vs 27% placebo (P 5 0.03) at wk 22 in patients with response during IP


ADAs

Cohen et al


10


Abbreviations: ADA, Antidrug antibody; ADM, adalimumab; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CG, continuous group; CI, confidence interval; CRP, C-reactive protein; CZP, certolizumab pegol; DIG, drug-interruption group; IFX, infliximab; IV, intravenous; IP, induction phase; MP, maintenance phase; NS, not significant; NTZ, natalizumab; OR, odds ratio; R1, regimen 1; R2, regimen 2; R3, regimen 3; R4, regimen 4; SC, subcutaneous; UTK, ustekinumab; VDZ, vedolizumab. Moderate to severe disease: baseline CDAI between 220 and 450. Response: decrease of $70 points in CDAI.14,17-20,23,28-34,40 Response: decrease of $3 points in Harvey-Bradshaw Index.25,26 Response: reduction of $50% in the number of draining fistulas during consecutive visits $4 weeks apart.15 Response (pediatric): decrease of $15 points in pediatric Crohn’s disease activity index (PCDAI) with final PCDAI #30.16 Enhanced response: decrease of $100 points in CDAI.12,17-20,23,24,29,30,32-34,40 *All trials were randomized, double blind, and placebo controlled unless otherwise mentioned. † Inconclusive: presence of drug together with ADAs prevents the correct quantification of ADAs based on the respective assays used.



Table III. Efficacy of biologics in placebo-controlled trials in UC Clinical trial* and patient characteristics ACT 1, Rutgeerts et al35 Moderate to severe active UC

ACT 2, Rutgeerts et al35 Moderate to severe active UC

Treatment regimens IV induction with IFX 5 mg/kg at wk 0, 2, and 6 R1: IFX 5 mg/kg every 8 wk thereafter until wk 46 R2: IFX 10 mg/kg every 8 wk thereafter until wk 46 R3: placebo every 8 wk thereafter until wk 46

R1: IV IFX 5 mg/kg at wk 0, 2, and 6, and every 8 wk thereafter until wk 22 R2: IV IFX 10 mg/kg at wk 0, 2, and 6, and every 8 wk thereafter until wk 22 R3: IV placebo at wk 0, 2, and 6, and every 8 wk thereafter until wk 22

PURSUIT-SC, Sandborn et al38 Moderate to severe active UC

R1: SC GLM 200 mg at wk 0 and 100 mg at wk 2 R2: SC GLM 400 mg at wk 0 and 200 mg at wk 2 R3: placebo

SC placebo or ADM 160 mg at wk 0, 80 mg at wk 2, and 40 mg every 2 wk thereafter until wk 52

69% in R1, 62% in R2, and 37% in placebo (all, P , 0.001) at wk 8

39% in R1 (P , 0.001), 32% in R2 (P 5 0.002), and 15% in placebo at wk 8 Sustained remission: 23% in R1 and 26% in R2 vs 8% in placebo (all, P , 0.001) between wk 8 and wk 30 Sustained remission: 20% in R1, 20% in R2, and 7% in placebo (all, P 5 0.002) between wk 8, wk 30, and wk 54


34% in R1, 28% in R2, and 8% in placebo (all, P , 0.001)


Sustained response: 49% in R1, 46% in R2, and 23% in placebo (all, P , 0.001) between wk 8 and wk 30 Sustained response: 39% in R1, 37% in R2, and 14% in placebo (all, P , 0.001) between wk 8, wk 30, and wk 54 Mucosal healing: 62% in R1, 59% in R2, and 34% in placebo (all, P , 0.001) 64% in R1, 69% in R2, and 29% in placebo (all, P , 0.001) at wk 8 Sustained response: 41% in R1, 53% in R2, and 15% in placebo (all, P , 0.001) between wk 8 and wk 30 Mucosal healing: 60% in R1, 62% in R2, and 31% in placebo (all, P , 0.001) 52% in R1, 55% in R2, and 45% in placebo (NS for all) at wk 8 Mucosal healing: 38% in R1, 47% in R2, and 42% in placebo (NS for all) at wk 8 50% vs 35% in placebo (P , 0.001) at wk 8 30% vs 18% in placebo (P 5 0.002) at wk 52 Mucosal healing: 41% vs 32% in placebo (P 5 0.032) at wk 8 Mucosal healing: 25% vs 15% in placebo (P 5 0.009) at wk 52 52% in R1, 55% in R2, and 30% in placebo (all, P , 0.0001) at wk 6 Mucosal healing: 43% in R1, 45% in R2, and 28% in placebo (P , 0.001 for all) at wk 6

ADAs

Sustained remission: 15% in R1, 22% in R2, and 2% in placebo (all, P , 0.001) between wk 8 and wk 30

10% in R1 (NS vs placebo), 18% in R2 (P 5 0.031 vs placebo), and 9% in placebo at wk 8

Data not provided

16% vs 9% in placebo (P 5 0.019) at wk 8 17% vs 8% in placebo (P 5 0.004) at wk 52

2.9% positive

19% in R1, 18% in R2, and 6.3% in placebo (all, P , 0.0001) at wk 6

0.4% positive at wk 6

(Continued)

11

R1: ADM 80 mg, then 40 mg R2: ADM 160 mg, then 80 mg R3: placebo


Cohen et al

ULTRA 1, Reinisch et al36 Moderate to severe active UC Loss of response or intolerance to oral corticosteroids and/or immunomodulators ULTRA 2, Sandborn et al37 Moderate to severe active UC Loss of response or intolerance to oral corticosteroids and/or immunomodulators


12

Table III (Continued )

39

Treatment regimens

PURSUIT-M, Sandborn et al Moderate to severe active UC Responded to GLM induction

R1: SC GLM 50 mg every 4 wk R2: SC GLM 100 mg every 4 wk R3: placebo

Feagan et al40 Moderate to severe active UC

IV infusions d 1 and d 29 R1: VDZ 0.5 mg/kg R2: VDZ 2.0 mg/kg R3: placebo

Parikh et al41 Moderate to severe active UC

IV infusions d 1, 15, 29, and 85 R1: VDZ 2 mg/kg R2: VDZ 6 mg/kg R3: VDZ 10 mg/kg R4: placebo IV induction with placebo or VDZ 300 mg at wk 0 and wk 2 Maintenance in patients with response at wk 6 R1: VDZ every 8 wk R2: VDZ every 4 wk R3: placebo every 4 wk

GEMINI 1, Feagan et al11 Moderate to severe active UC



47% in R1 (P 5 0.010 vs placebo), 51% in R2 (P , 0.001 vs placebo), and 31% in placebo at wk 54 Mucosal healing: 42% in R1 (NS vs placebo), 44% in R2 (P 5 0.001 vs placebo), and 27% in placebo at both wk 30 and wk 54 66% in R1, 53% in R2, and 33% in placebo (all, P 5 0.002) at wk 6

24% in R1 (NS vs placebo), 29% in R2 (P 5 0.003 vs placebo), and 15% in placebo at both wk 30 and wk 54

2.9% positive through wk 54

24% positive overall by wk 8 38% positive in R1 by wk 8 11% positive in R2 by wk 8

Mean decrease in PMS: 51% in VDZ combined vs 13% in placebo at wk 6

33% in R1, 32% in R2, and 14% in placebo (all, P 5 0.02) at wk 6 Endoscopic remission: 28% in R1, 12% in R2, and 8% in placebo (P 5 0.007 for VDZ overall vs placebo) at wk 6 58% in VDZ combined vs 50% in placebo at d 43 (P value, data not provided)

11% positive Peak titer: 1:15,625 at d 113 and d 141 in 1 patient

47% vs 25% in placebo (P , 0.001) at wk 6 Mucosal healing: 41% vs 25% in placebo (P 5 0.001) at wk 6

17% vs 5% in placebo (P 5 0.001) at wk 6 42% in R1, 45% in R2, and 16% in placebo (all, P , 0.001) at wk 52

3.7% positive at any point through wk 52 1.0% persistently positive ($2 consecutive pt) through wk 52

ADAs


Abbreviations: ADA, Antidrug antibody; ADM, adalimumab; GLM, golimumab; IFX, infliximab; IV, intravenous; NS, not significant; PMS, Partial Mayo score; R1, regimen 1; R2, regimen 2; R3, regimen 3; R4, regimen 4; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab. Moderate to severe active disease: baseline Mayo Clinical Score (MCS) $6 points and endoscopic subscore $2 points. Response: decrease of $3 points in MCS and decrease of $30% of baseline MCS.11,35-40 Response: decrease of $2 points in PMS and decrease of $25% of baseline PMS.41 Remission: MCS #2 points with no subscore .1 point.11,35-40 Remission: PMS #2 points with no subscore .1 point.41 Remission: UC clinical score of #1 point and a modified Baron score of #1 point, with no evidence of rectal bleeding.40 Endoscopic response: improvement in modified Baron score of $2 points.40 Endoscopic remission: modified Baron score of 0 point.40 Mucosal healing: Mayo endoscopy score $1 point.11,35,38,39 Mucosal healing: absence of mucosal ulceration.21 *All trials were randomized, double blind, and placebo controlled unless otherwise mentioned.

Cohen et al


Study

Patient characteristics and treatment regimens

Main efficacy findings

Zorzi et al42

Moderate to severe CD IV IFX 5 mg/kg at wk 0, 2, and 6, and every 8 wk thereafter until wk 52 SC ADM 160 mg at wk 0, 80 mg at wk 2, 40 mg at wk 6, and 40 mg every 2 wk thereafter until wk 52

Russo et al43

Real-life data Moderate to severe CD Various regimens of ADM

IFX: 70% remission, 5% improvement, 25% no response at wk 6 IFX: lower CDAI levels at wk 2 and wk 6 vs wk 0 (P , 0.0001 for all) among patients completing IFX induction IFX: 74% remission, 3% improvement, 13% worsening, and 10% loss of response at wk 54 ADM: 66% remission, 14% improvement, 20% no response at wk 4 ADM: 73% remission, 2% improvement, 17% worsening, and 8% loss of response at wk 54 ADM: lower CDAI levels at wk 4, 12, 30, and 54 vs wk 0 (P , 0.001 for all) among patients competing ADM maintenance Sustained response: 84%, for an average of 8.6 months

Nichita et al44

Real-life data Moderate to severe CD Various regimens of ADM

Swoger et al45

Moderate to severe CD Previous IFX exposure Various regimens of ADM

Russell et al46

Moderate to severe pediatric CD ADM 80 mg at wk 0 and 40 mg at wk 2, and 40 mg every 2 wk thereafter Moderate to severe CD Loss of response or intolerance to IFX Various regimens of ADM Moderate to severe active CD IFX naive or IFX experienced SC ADM 160 mg at wk 0, 80 mg at wk 2, and 40 mg every 2 wk thereafter

Sprakes et al47

Pannaccione et al48

Barreiro-de-Acosta49

Moderate to severe CD with extraintestinal manifestations SC ADM 160 mg at wk 0, 80 mg at wk 2, and 40 mg every 2 wk thereafter


Table IV. Efficacy of biologics in open-label trials

Initial response: 8%, lost after an average of 9 mo No response: 8% Response: 84% at w, 6 Remission: 53% at wk 4–6 Sustained remission: 90% through wk 12, 72% through wk 24, and 45% through w, 52 Response (cessation of diarrhea and abdominal cramping, closing of draining fistula): 45% Partial response (reduction of the amount of diarrhea and abdominal cramping, decrease in the drainage, size or number of fistula): 37% No response: 18% Remission: 24% at mo 1, 58% at mo 6, and 41% at mo 12 Response: 77% Sustained response: 64% at last time of follow-up

(Continued)

Cohen et al

Remission: 36% in IFX-experienced patients (P , 0.01 vs baseline) and 53% in IFXnaive patients (P , 0.001 vs baseline) at wk 24 Fistula healing: 26% in IFX-experienced patients and 48% in IFX-naive patients at wk 12 Fistula healing: 28% in IFX-experienced patients and 60% in IFX-naive patients (P , 0.01) at wk 24 CD response: 43% at mo 6 Extraintestinal manifestations response: 28% at mo 6 CD remission: 33% at mo 6 Extraintestinal manifestations remission: 38% at mo 6

13

Hyams et al50

€fberg et al51 Lo Baert et al52

Schoepfer et al53

Vavrika et al54

buterne et al55 He

Patient characteristics and treatment regimens

Main efficacy findings

Open-label trial Moderate to severe pediatric CD SC ADM induction at wk 0 and wk 2 with 160 mg or 80 mg for body weight $40 kg and 80 mg or 40 mg for body weight ,40 kg SC ADM maintenance therapy based on body weight with high dose (40 mg or 20 mg) or low dose (20 mg or 10 mg) Moderate to severe CD SC ADM 180 mg at wk 0, 60 mg at wk 2, and 40 mg every 2 wk thereafter Real-life data Moderate to severe CD Various regimens of ADM, including dose escalation and dose de-escalation Moderate to severe CD Complicated disease behavior SC CZP 400 mg at wk 0, 2, and 4 Moderate to severe CD Complicated disease behavior SC CZP 400 mg at wk 0, 2, and 4, and every 4wk thereafter until wk 24 Moderate to severe active ileocolonic CD, with ulceration in $2 intestinal segments with a CDEIS $8 pt

Clinical remission: 34% at wk 26, with 39% in high-dose group and 28% in lowdose group (not significant)

SC CZP 400 mg at wk 0, 2, and 4, and every 4 wk thereafter until week 52

Sandborn et al33

Parikh et al56

Hyams et al57

Oussalah et al58

Moderate to severe CD Primary nonresponse to IFX IV UTK 4.5 mg/kg at wk 0 or SC UTK 90 mg at wk 0, 1, 2, and 3 Moderate to severe CD or active UC, or patients with UC who already completed 8 mo of VDZ IV VDZ 2, 6, or 10 mg/kg on d 1, 15, and 43, and every 8 wk thereafter Pediatric (#16 y age) UC Continuous IFX therapy in 65% of sample Episodic IFX therapy in 21% of sample Adult UC At least one IFX infusion

Cohen et al

Study

14

Table IV (Continued )

Remission: 52% at wk 20 Extraintestinal manifestations remission: 51% at w, 20 Response: 84% at wk 4 Response to dose escalation for an additional 6 mo in patients who lost initial response: 67% Significant decrease in HBI (P , 0.0001) at wk 6 Response: 54% at wk 6 Remission: 40% at wk 6 Significant decrease in HBI (P , 0.0001) at wk 24 Response: 70% at wk 6 and 67% at wk 26 Remission: 40% at w, 6 and 37% at wk 26 Mean change in CDEIS compared with baseline: 25.7 pt at wk 10 and 24.7 pt at wk 54 (both, P , 0.0001) Endoscopic response (decrease in CDEIS .5 pt): 54% at wk 10 and 49% at w, 54 Endoscopic remission (CDEIS ,6 pt): 37% at wk 10 and 27% at wk 54 Complete endoscopic remission (CDEIS ,3 pt): 10% at wk 10 and 14% at wk 54 Mucosal healing (absence of ulceration): 7% at wk 10 and 8% at wk 54 Response: 48% at wk 6 Enhanced response: 41% at wk 6 Remission: 22% at wk 6 Response: 39% overall, 39% in UC, and 37% in CD Remission: 58% overall, 72% in UC, and 21% in CD


Inactive disease without steroid use: 26% at mo 3, 27% at mo 6, 38% at mo 12, and 21% at mo 24 Likelihood of avoiding colectomy: 61% in overall population and 74% in population receiving continuous IFX at mo 24 22% nonresponders after induction 44% experienced IFX failure after induction Probability of maintaining IFX failure-free survival: 66% at 1 y, 53% at 2 y, 41% at 3 y, and 27% at 6 y Probability of maintaining colectomy-free survival: 84% at 1 y, 78% at 2 y, 76% at 3 y, and 61% at 6 y Probability of maintaining hospitalization-free survival: 67% at 1 y, 60% at 2 y, 57% at 3 y, and 45% at 6 y

Abbreviations: ADM, adalimumab; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; CZP, certolizumab pegol; HBI, HarveyBradshaw Index; IFX, infliximab; IV, intravenous; SC, subcutaneous; UC, ulcerative colitis; UTK, ustekinumab; VDZ, vedolizumab.

Response: 75% at wk 8 Remission: 40% at wk 8 Mucosal healing: 68% at wk 8 Response: 38% in IFX every 8 wk vs 12% in IFX every 12 wk at wk 54 7.7% antidrug antibody positive by wk 52 Hyams et al61

IV IFX 5 mg/kg at wk 0, 2, and 6, and every 8 wk thereafter

Cohen et al

Moderate to severe active UC Loss of response to IFX Various regimens of ADM Moderately severe to severe active pediatric UC No response to conventional therapies IV IFX 5 mg/kg at wk 0, 2, and 6 If response achieved at wk 8, patients randomized to IV IFX 5 mg/kg every 8 wk or 10 wk Taxonera et al60

Seow et al59

Moderately severe to severe active UC

Response: 59.1% overall, 70% in moderate UC, and 41% in severe UC (P 5 0.004) during induction phase Response: 60% in moderate UC and 29% in severe UC (P 5 0.003) during maintenance phase Remission: 32.2% overall, 41% in moderate UC, and 17% in severe UC (P 5 0.046) during induction phase Remission: 45% in moderate UC and 19% in severe UC (P 5 0.009) during maintenance phase Response: 53% at wk 4 and 60% at wk 12 Remission: 10% at wk 4 and 27% at wk 12


15

in Chinese males.67 When given the same dose, subjects weighing more than 100 kg achieve lower serum concentrations than subjects weighing 100 kg or less. UTK does not accumulate in serum when administered every 12 weeks.13 Tables II 12,14-34 and III11,35-41 describe the characteristics of placebo-controlled clinical trials involving biologics in patients with IBD in terms of efficacy and the development of anti-drug antibodies (ADAs). All 7 biologics used in IBD showed superior response, enhanced response, remission, and mucosal healing rates to placebo. Table IV provides comparative results from open-label trials and real-life patient cohorts.33 EFFICACY OF BIOLOGICS IN CD Infliximab. Several early, randomized, double-blind, placebo-controlled trials provide information with respect to IFX efficacy. Patients with CD with an initial response to IFX have increased chances of achieving a sustained response for longer periods of time if IFX is maintained.14,15 Clinical benefits are generally maintained throughout open-label extension studies.16,68 Better response and remission rates were obtained during MP by administering IFX every 8 weeks compared with every 12 weeks in CD16; however, no dose effect was observed.14 The preferred IFX maintenance regimen in pediatric patients with CD with response to induction therapy should be every 8 weeks.16 In a randomized, double-blind trial, the combination of IFX and the immunosuppressant agent azathioprine showed superior efficacy to either drug alone.69,70 The combination treatment was associated with greater rates of corticosteroid-free clinical remission at week 26 than either IFX or azathioprine alone (57% vs 44%, P 5 0.02 and vs 30%, P , 0.001, respectively), as well as greater rates of mucosal healing (44% vs 30%, P 5 0.06 and vs 16%, P , 0.001, respectively).69 Disease duration and severity predict clinical benefit further. CD of shorter duration (2 years or less) was a predictor of mucosal healing compared with CD of longer duration (.2 years; P 5 0.013).70 Adalimumab. Response rates at week 4 ranged between 52% and 70% in patients with CD treated with ADM, with a trend toward a linear dose-dependent effect.22 In contrast, the ADM dose had no effect on CD remission rates at week 4, which ranged between 18% and 36% in another study.17 Differences in remission rates between ADM and placebo begin at week 6 and are generally sustained throughout the follow-up period.20 Response, enhanced response, and remission rates were sustained through week 56 in

16

Cohen et al

approximately 85% of patients with CD, with clinical benefits at week 4, as well as in approximately 45% of the overall sample treated with ADM.18,20 These rates are slightly less than the ones at week 26.20 Clinical remission was maintained through week 52 in another study as well, with half this population being able to become steroid free.71 ADM can maintain remission for as long as 2–3 years, based on data from the ADHERE trial, a long-term follow-up of patients included in the CHARM trial. Modest rates of steroid-free remission were also maintained. These results were superior for patients placed initially on weekly ADM, which corresponded to greater initial response and remission rates.72,73 Rates of complete endoscopic healing at week 52 reached 23% in a small sample of patients with CD treated with ADM. However, endoscopic healing is not accompanied by corresponding decreases in messenger RNA levels of TNF and interleukin 17A in the majority of these patients.74 ADM is also effective in inducing remission in pediatric patients with CD, with a trends toward better clinical outcomes in patients receiving higher doses.50 ADM is more effective in anti-TNF-naive patients compared with patients with prior exposure to antiTNF treatment, especially in the short term.20,22,37,51 Loss of response to IFX was a risk factor for not achieving remission at weeks 4–6 of ADM treatment, compared with IFX intolerance.44,75 Higher induction doses of ADM (160 mg/80 mg) did not differ from lower doses (80 mg/40 mg) with respect to early response rates among patients with CD with loss of response or intolerance to IFX.18,19,22 Prior exposure to anti-TNF treatment did not affect significantly the rate of steroid-free disease remission in another study.42 ADM is superior to placebo in patients with CD with loss of response or intolerance to IFX.19 Furthermore, ADM remains superior to placebo regardless of baseline C-reactive protein concentration. Concomitant immunosuppressive treatment predicts higher odds of remission (P 5 0.003).46 In contrast, smoking (P 5 0.02) and structuring or penetrating disease behavior (P 5 0.01) are negative predictors of steroid-free disease remission in patients with CD.42 Younger age predicts better extraintestinal manifestation response (P 5 0.04).49 ADM dose escalation and de-escalation have high success rates in patients who lose an initial response to ADM. Dose escalation can help reinduce clinical benefits. Dose de-escalation was successful in 63% of patients in whom dose escalation was beneficial.52 Predictors of need for ADM dose escalation include previous anti-TNF use (P , 0.0001), lack of concomitant azathioprine use (P 5 .02), and elevated baseline Creactive protein levels (P , 0.05).52


In long-term, open-label ADM follow-up, sustained remission rates were greater for patients with disease of shorter duration. In an analysis classifying patients with early CD according to disease duration at baseline, ADM was superior to placebo in terms of remission at weeks 26 (33% vs 14%, P , 0.001 overall, P 5 0.008 for disease duration less than 2 years, not significant for disease duration of 2–5 years, and P , 0.001 for disease duration 5 years or more) and 56 (30% vs 10%, P , 0.001 overall, P 5 0.024 for disease duration of less than 2 years, P 5 0.028 for disease duration of 2– 5 years, and P , 0.001 for disease duration of 5 years or more). Similar trends were observed for clinical response.76 Certolizumab pegol. The efficacy of CZP was compared with that of placebo in the PRECISE trials.23-26 CZP was associated with modest improvements in clinical response compared with placebo, but not remission, at week 4.23 However, CZP maintenance therapy was associated with sustained response and remission among patients with response to CZP induction,24 whereas continuous therapy is preferred over interrupted (ie, placebo during MP) therapy.25 Last, administration of an additional CZP dose in patients who relapse while on CZP maintenance therapy, as well as reintroduction of CZP in patients who relapse on placebo maintenance therapy, are useful strategies of regaining disease control.26 CZP was also effective in real-life cohorts of moderate to severe CD with complicated disease behavior during both IP and MP.53,54 In the MUSIC trial, which assessed patients with moderate to severe CD and multiple ulcerations, CZP leads to healing of endoscopic lesions, as assessed by decreases in the Crohn’s Disease Endoscopic Index of Severity score.55 Endoscopic response and remission rates at both week 10 and week 54 were associated significantly with CZP plasma levels.77 Natalizumab. NTZ leads to significant decreases in the Crohn’s Disease Activity Index by week 2.27 No dose-response relationship is observed with NTZ, because saturation of a4 integrins on peripheral blood leukocytes occurs below the recommended NTZ dose in CD, around 1 mg/kg.28 Although NTZ induction leads to clinical benefits that are not significantly different from placebo, NTZ maintenance was superior to placebo in terms of response and remission rates. Significant differences between NTZ and placebo are observed at all time points between week 20 and week 60.29 NTZ induction was associated with early and sustained response, and remission in another study.30 The discrepancies between the 2 trials can be explained in part by unusually high early response and


remission rates in placebo in the former study, whereas these rates were lower in the latter. Furthermore, cotreatment with NTZ shows trends toward better outcomes in patients with CD with disease not controlled effectively by IFX alone.31 Vedolizumab. VDZ is superior to placebo in both UC and CD, with similar effects between the 2 entities of IBD. VDZ is associated with dose-dependent effects on remission during IP in patients with CD.32 Enhanced response rates were similar between VDZ and placebo during IP in patients with CD.12 VDZ was significantly superior to placebo in terms of remission during MP.12 Ustekinumab. UTK was generally superior to placebo in a short-term cross-over study. It is, however, difficult to interpret these results because of the long UTK t1/2 and high initial response rates in placebo, along with a small sample size.33 UTK was superior to placebo in terms of response, enhanced response, and remission at week 22 in patients with CD in a separate trial.34 Intravenous UTK appears slightly superior to subcutaneous UTK.33 EFFICACY OF BIOLOGICS IN UC Infliximab. Response, remission, and sustained response rates at week 8 (2 weeks after the last IP infusion) were similar in 2 moderate to severe UC cohorts, whereas a 10-mg/kg dose was superior to 5 mg/kg.35 A lack of early response predicts future treatment failure. No clinical response after IFX induction was the primary determinant of treatment failure (hazard ratio [HR], 8.12) and first hospitalization (HR, 3.87) in an adult UC sample,58 whereas a lack of endoscopic remission at month 3 was the primary determinant of colectomy in another UC sample (P 5 0.02).78 On the other hand, IFX maintenance therapy was associated with more than 90% odds of having no or mild disease symptoms at any given time in a 3-year extension study among patients with UC who achieved initial clinical benefits.79 IFX treatment should be maintained through MP and cannot be substituted with placebo. Continuing IFX treatment was associated with high rates of clinical benefit in a 3-year follow-up study of the ACT 1 and ACT 2 cohorts. Moreover, scheduled maintenance dosing is recommended, because episodic (on-demand) treatment was the primary determinant of IFX failure (HR, 12.09) in an adult UC sample.58,79,80 IFX was associated with a lesser need for colectomy compared with placebo in a small study of patients with moderate to severe active UC not responding to conventional treatments.81 Moderately severe UC was associated with greater odds of achieving clinical

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response and remission, and endoscopic remission during both IP and MP compared with severe UC.59 Overall, IFX shows better response (REACH vs ACT) and remission (ACCENT I vs ACT 1) rates in CD than in UC.14,16,35 Adalimumab. ADM was superior to placebo in patients with moderate to severe UC without adequate response to conventional therapies. Differences were significant between ADM and placebo regardless of previous anti-TNF exposure, with the exception of remission at week 8. However, response rates at week 52 and remission rates through week 52 are less in patients with UC compared with patients with CD.36,37 Response, remission, and mucosal healing during ADM induction predict sustained clinical benefits at week 52.82 Early clinical response (week 12) further predicts a lack of future need for colectomy.60 A positive correlation is generally found between serum ADM levels and clinical remission in patients with moderate to severe UC.82 However, a high degree of variability in serum ADM levels was observed, with overlap between patients who achieved remission and those who did not.83 Both IFX and ADM induced and maintained a response among patients with UC who lost a response to traditional therapy.84 ADM shows a trend toward better response rates during induction than IFX in a small sample of anti-TNF-naive patients with UC (P 5 0.0889). Response rates between the 2 drugs were similar during MP.84,85 There were no differences in the rates of steroid-free disease remission between patients treated with IFX or ADM.42 Although differences between ADM and placebo (eg, ULTRA 1 and ULTRA 2) are less pronounced than differences between IFX and placebo in similarly designed clinical trials (ACT 1 and ACT 2), it is important to note that ADM cohorts are made up of patients who may have been medicated previously with IFX, whereas IFX cohorts are made up of anti-TNF-naive patients.37 Golimumab. GLM induces clinical response, remission, and mucosal healing by week 6, and maintains these benefits through week 54 in patients with UC.38,39 Vedolizumab. Phase III trials have demonstrated the efficacy of VDZ for the induction of clinical remission, clinical response, and mucosal remission in patients with moderate to severe active UC treated previously with other agents such as corticosteroids, purine antimetabolites, and/or TNF-a inhibitors. Its clinical benefits were superior to those of placebo at week 6. Superior remission rates were maintained at week 52.11,41,86 There were no significant differences between VDZ every 4 weeks and VDZ every 8 weeks during MP.11

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SERUM TROUGH CONCENTRATION AND IMMUNOGENICITY

Although pharmacokinetic parameters like Cmax and AUC are dependent primarily on the dose administered and on the dosing frequency used, the serum drug level before each infusion—a parameter known as trough concentration (Ctrough)—is influenced by elimination. The efficacy of biologics administered periodically is linked strongly to its Ctrough and to the production of ADAs—a process referred to as immunogenicity. ADAs form under conditions of low serum drug concentration. Indeed, an undetectable serum IFX Ctrough level precedes the formation of ADAs, whereas ADAs can, in turn, accelerate the clearance of a drug throughout the treatment period, giving rise to persistently low or undetectable Ctrough levels. This leads to subtherapeutic drug levels and treatment failure. Ctrough is, thus, a very important pharmacologic parameter, because a strong relationship exists between low Ctrough and insufficient clinical response. Therapeutic drug monitoring can help optimize the treatment, ensuring adequate drug levels are maintained.59,87 Four patterns of insufficient clinical response in IBD have been identified, based on the presence of low Ctrough and/or ADAs, and different strategies are used in each situation to regain disease control. The first of these is characterized by low Ctrough levels without significant ADA formation, in which situation altered kinetics leads to decreased bioavailability. Patients can, in theory, benefit from increasing the dose of the drug or from decreasing the dosing interval. In the second situation, low Ctrough levels are measured in the presence of high ADA levels. ADAs can prevent the drug from entering circulation or can increase its clearance through the formation of immune complexes. Patients may benefit from a treatment change to a biologic to which they have not yet developed ADAs. The third pattern of insufficient response is characterized by high Ctrough levels with low ADA formation, a situation thought to be brought about by a disease pattern in which the target molecule plays a minor role. In these patients, dose escalations are unlikely to help, and a change to a different treatment strategy may be beneficial. Last, situations marked by high Ctrough and ADA levels may result from laboratory techniques that identify ADAs with low clinical relevance. Nonetheless, a change to a different treatment strategy is likely to help.88-90 Additional factors associated with anti-TNF treatment failure in patients with IBD include body mass index, serum albumin concentration, concomitant immunosuppressive therapy, degree of systemic inflammation (TNF-a burden), and disease subtype (CD vs


UC).87 Other strategies to minimize immunogenicity include scheduled instead of episodic treatment, and combined therapy instead of monotherapy. The likelihood of ADA formation is thus decreased when monoclonal antibodies are administered as scheduled treatment with concomitant immunosuppressants.91 Infliximab. Loss of response to IFX can occur in as many as 70% of patients treated, and it results in a need for dose escalation or treatment modification. Immunogenicity is recognized as the primary determinant of loss of response to IFX.92 Because of its chimeric mouse-human nature, IFX is the biologic associated most often with immunogenicity.93 Human antichimeric antibodies are directed against the murine F(ab0 )2 fragment.63,92 ADAs can neutralize the function or increase the clearance of IFX, leading to low or undetectable Ctrough levels, and ultimately loss of response. IFX clearance was as much as 2.7 times greater, with an elimination t1/2 as much as 34% lower in ADA-positive patients.63,92 An undetectable IFX Ctrough (,0.1 mg/mL) is an important predictor of ADA positivity.6 Patients testing positive for ADAs have lower Ctrough levels than those negative for ADAs in several studies (3.3 6 4.6 mg/ mL vs 11.8 6 12 mg/mL, P , 0.001; 0.18 mg/mL vs 3.41 mg/mL, P , 0.001; 1.61 6 6.13 mg/mL vs 4.45 6 3.92 mg/mL, P , 0.0001).14,94-96 ADA positivity in patients taking IFX generally ranges from 3% to 15%,14,16,35,61,69 whereas ADA negativity ranges from 16% to 20%.16,35 The difference between these values is accounted for by inconclusive results, resulting from the presence of detectable IFX levels in serum at the time of measurement. IFX competes with ADAs for binding sites in the immunoassay used, preventing the accurate measurement of ADAs.14,16,35 Using an enzyme-linked immunosorbent assay with antihuman l chain conjugated antibody as the detector antibody, Ben-Horin et al94 measured separately serum IFX levels and ADAs to IFX, and showed that the presence of detectable IFX in sera was lower in ADApositive samples than in ADA-negative samples (33% vs 85%, P , 0.001). A strong relationship was found between IFX Ctrough levels and clinical outcomes. Greater rates of clinical remission (69% vs 15%, P , 0.001), endoscopic improvement (76% vs 28%, P , 0.001), and endoscopic remission (27% vs 8%, P 5 0.021), as well as lower odds of colectomy (7% vs 55%, P , 0.001) are associated with detectable serum IFX levels.59 A detectable IFX Ctrough concentration was a strong determinant of clinical remission (odds ratio [OR], 12.5; 95% confidence interval [CI], 4.6–33.9; P , 0.001) and endoscopic improvement (OR, 7.3; 95% CI, 2.9–18.4;


P , 0.001), whereas undetectable IFX Ctrough levels were a strong predictor for colectomy (OR, 9.3; 95% CI, 2.9–29.9; P , 0.001).59 In a systematic review of studies that measured serum ADAs to IFX, IFX Ctrough levels, and clinical outcomes in patients, Nanda et al92 conclude that the presence of ADAs is associated with significantly lower IFX Ctrough levels (P , 0.0001 in pooled analysis), as well as a high risk of loss of response (relative risk [RR], 3.2, 95% CI, 2.0–4.9, P , 0.0001 in pooled analysis; RR, 3.2, 95% CI, 1.9– 5.5, P , 0.0001 in patients with CD; RR, 2.2, 95% CI, 0.5–9.0, not significant in patients with UC; and RR, 6.9, 95% CI, 1.9–25.0, P , 0.003 in mixed samples). This was based largely on data from patients with CD, because the low number of patients with UC prevented statistical significance. However, a high degree of heterogeneity was noted between the methods used to measure ADAs, as well the criteria that defined clinical response.92 The greatest incidence of ADA positivity was observed in patients receiving lower IFX doses, especially in the group receiving placebo after IFX induction.14 The dosing schedule affects the formation of ADAs, with ADA positivity being greater in patients with CD receiving scheduled treatment compared with those receiving continuous treatment.93 As such, episodic treatment is a risk factor for ADA formation compared with continuous treatment (39% vs 16%, P 5 0.036).97 Ben-Horin et al94 found that it was significantly more likely to detect IFX in sera in patients negative for ADAs than it was in patients positive for ADAs (85% vs 33%, P , 0.001). Concomitant immunosuppressant treatment appears protective against both ADA formation and low Ctrough levels. Median Ctrough levels at week 30 were greater in patients with CD treated with IFX and the immunosuppressant agent azathioprine than in patients treated with IFX alone compared with IFX alone (3.5 mg/mL vs 1.6 mg/mL, P , 0.001), whereas the incidence of ADA positivity was less (0.9% vs 14.6%).69 Detectable IFX Ctrough levels are associated with greater odds of achieving clinical remission, as well as endoscopic improvement in patients with CD compared with undetectable IFX Ctrough levels, regardless of the presence of ADAs or concomitant immunomodulators.97 This study suggests that ADA positivity decreases IFX efficacy through its effects on IFX Ctrough levels, and that low IFX Ctrough levels are the actual cause of drug ineffectiveness, regardless of the mechanism that gives rise to this phenomenon. Response rates were similar in patients with ADAs and patients without ADAs in an early study.15 Patients with complete response had significantly greater IFX Ctrough levels compared with patients with partial or

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no response (9.8 mg/mL vs 3.0 mg/mL, P 5 0.056). A positive correlation was observed with IFX Ctrough levels and the odds of achieving complete response. Statistical significance was likely not achieved because of a low sample size.98 However, IFX Ctrough levels are not always predictive of loss of response. A retrospective analysis found that intensification of IFX treatment can lead to clinical response in patients with loss of response to IFX. There were no differences in the baseline Ctrough levels between patients who responded to treatment intensification and those who did not.96 Mean Ctrough levels can be as much as 10 times less in smokers compared with nonsmokers (P , 0.0001), and this is accompanied by a significantly greater incidence of ADAs to IFX (P 5 0.002), suggesting that smoking is a risk factor for disease relapse in both CD and UC.98 Smoking, especially current smoking, is a risk factor for low IFX Ctrough levels and a greater incidence of ADA positivity, as well as treatment nonresponse.42,98,99 Adalimumab. After a 160-mg/80-mg loading dose in CD and UC, the mean ADM Ctrough level at weeks 2 and 4 was 12 mg/mL. During MP, the mean steadystate Ctrough level was 7 mg/mL in CD cohorts and 8 mg/mL in UC cohorts at weeks 24 and 56 after a 40mg every-2-week dosing regimen, and 15 mg/mL at week 52 in UC cohorts after a 40-mg weekly dosing regimen.7 Karmiris et al100 observed fluctuating median ADM Ctrough levels over time in patients with CD, ranging from 8.6 mg/mL (range, 6.5–10.8 mg/mL) at week 2, 5.3 mg/mL (range, 2.8–10.9 mg/mL) at week 4, 7.9 mg/ mL (range, 3.2–12.0 mg/mL) at week 12, 7.8 mg/mL (range, 1.8–12.2 mg/mL) at week 24, and 10.7 mg/mL (range, 6.1–18.1 mg/mL) at week 54.100 ADA positivity was associated with persistently lower median ADM Ctrough levels throughout the entire follow-up period in a prospective study. A Ctrough level less than 0.33 mg/ mL at any time is a risk factor for less sustained clinical benefit (P 5 0.01). This relationship appears to hold true during MP only, because no relationship between Ctrough and ADAs to ADM was found before week 4.100 A separate study reports that all patients were either negative for ADAs or results were inconclusive during IP at week 4.19 ADA positivity ranged from 2.6% to 6% by week 52–54.18,20,37,50 Interestingly, ADA-positive patients were found in both high and low doses, in the presence or absence of immunosuppressant treatment, and either did or did not achieve remission in an open-label trial of pediatric patients with CD.50 ADA positivity was encountered among 44% of patients who lost response to ADM in 1 study.101

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The Ctrough level was relatively consistent through weeks 26–52 during ADM MP in a pediatric CD sample, in which ADA positivity was evaluated at 3.3%.50 ADM Ctrough levels were consistently higher among patients with UC who achieved remission compared with those with active disease at week 8 (11.4 6 5.15 mg/mL vs 8.49 6 4.35 mg/mL), week 32 (10.6 6 5.64 mg/mL vs 6.95 6 3.98 mg/mL), and week 52 (10.8 6 7.45 mg/mL vs 6.18 6 4.22 mg/mL).37 A similar relationship was also found in another study (6.02 mg/mL vs 3.2 mg/ mL, P 5 0.0120).102 Greater Ctrough levels correlate well with remission (P 5 0.012) and mucosal healing (P , 0.005) in mixed CD and UC samples. In addition, mucosal healing was more common among ADAnegative patients. ADA positivity was also more common in patients with active disease.102 Concomitant immunosuppressive therapy is often protective against ADA formation.18 Presence of ADAs correlated with undetectable serum ADM levels and no remission in another study.22 In samples made up of both anti-TNF-naive and -experienced patients, a 160-mg/80-mg induction regimen led to greater Ctrough levels at week 4 (P , 0.0001), more frequent (P 5 0.004) and more sustained clinical benefits (31.8 weeks vs 12.0 weeks, P 5 0.04), less frequent primary nonresponse (OR, 0.02; P , 0.0001), faster withdrawal of immunosuppressants (8.9 months vs 22.8 months, P 5 0.01), and fewer ADAs to ADM (5.7% vs 17.9%, P 5 0.05) than a 80-mg/40-mg induction regimen.100 Patients who lost their initial response to ADM received dose escalations, and this increased ADM Ctrough levels (P 5 0.001) and correlated well with clinical response (P , 0.0001). Therapy discontinuation at either 24 weeks or 54 weeks was associated with low ADM Ctrough levels at these time points.100 Karmiris et al100 also found that patients who developed ADAs to ADM at any point throughout the study had consistently low median ADM Ctrough levels, regardless of the time point when ADAs were detected. Having an ADM Ctrough level less than 0.094 mg/mL was a risk factor ADA positivity and ADM discontinuation.100 Certolizumab pegol. More limited data are available for other biologics. For these agents, data are often limited to the findings from their respective clinical trials. In the PRECISE trials, the incidence of ADAs to CZP was 8% at weeks 26–28 among patients treated continuously.23-25 Drug interruption was associated with an increased incidence of ADAs.25 In turn, presence of ADAs was associated with lower mean CZP plasma concentrations.25,26 Ctrough levels remained relatively constant between week 4 after the last CZP induction dose and week 80 in the CZP continuous group (6.9 mg/mL and 7.7 mg/mL,


respectively). Reintroduction of CZP at week 32 following drug interruption after IP also rescued CZP Ctrough levels at week 80 (6.0 mg/mL).25 Reintroduction of CZP after treatment failure resulted in mean CZP plasma concentrations remaining relatively constant beginning at week 8, as long as the patient remained negative to ADAs.26 ADAs did not develop by week 52 in a small sample.77 ADA development is not associated with a loss of efficacy in CZP patients. Concomitant therapy with immunosuppressive agents and continuous CBZ were protective against ADA formation.24,103 Golimumab. The mean steady-state GLM Ctrough levels were 1.8 6 1.1 mg/mL in patients with UC.9 Stable-state Ctrough levels were reached 8 weeks into MP, and they remained stable through week 44, with a median Ctrough level of 0.69–0.83 mg/mL in GLM 50 mg every 4 weeks, and 1.33–1.58 mg/mL in GLM 100 mg every 4 weeks.39 Response through week 52 and sustained remission at weeks 32–54 were more common in patients with higher serum concentrations at these time points.39 GLM was associated with low rates of ADA formation in healthy volunteers.65,66 ADA positivity ranged from 0.4% at week 6 in 1 study to 2.9% at week 54 in another in patients with UC.38,39 Concomitant immunosuppressive therapy was protective against ADAs to GLM development.39 Natalizumab. The average steady-state NTZ Ctrough level was 10 6 9 mg/mL, and this was achieved 16– 24 weeks after each dose.10 NTZ serum levels remain relatively constant over time, with little to no accumulation between infusions.31 IFX and NTZ had no effect on one another’s serum levels.31 ADA positivity ranged from 4% to 11% by weeks 10– 12 in patients taking NTZ.28-31 Two patients were transiently positive for ADAs at 1 visit by week 12 in a small trial, 1 of whom achieved and maintained remission by week 12 whereas the other showed no response by week 8.27 Replacing NTZ with placebo is associated with a greater incidence of ADAs to NTZ than continuous treatment with either NTZ or placebo.28 Although transient ADAs or negative ADAs show similar response rates, persistent ADAs are associated with loss of response by week 60.29,30 Concomitant immunosuppressive and corticosteroid therapy was protective against developing ADAs to NTZ.29,30 Vedolizumab. The mean VDZ Ctrough levels at week 6 were 27.9 6 15.5 mg/mL in patients with UC and 26.8 6 17.5 mg/mL in patients with CD.11,12 ADA positivity ranged from 3.7% to 4.1% at week 52 in the GEMINI 1 and 2 trials. Concomitant immunosuppressive therapy was protective against


developing ADAs to VDZ.11,12 Higher incidences of ADA positivity are reported in other studies, although the clinical consequences are unclear.40,41 ADA positivity results in unsaturation of a4b7 binding sites on circulating CD41CD45RO1 T lymphocytes.40 Remission rates were lower in VDZ patients positive for ADAs (12%) compared with patients negative for ADAs or with low titers (42%) in an earlier study using different doses and smaller samples.40 Ustekinumab. The mean, steady-state UTK Ctrough levels were 0.31 6 0.33 mg/mL with a 45-mg dose and 0.64 6 0.64 mg/mL with a 90-mg dose. Steadystate concentration was achieved by week 28. UTK Ctrough levels are comparable between subjects weighing more than 100 kg receiving a 90-mg dose and subjects weighing 100 kg or less receiving a 45mg dose.13 ADA positivity was observed in less than 1% of the patients treated with UTK in 2 placebocontrolled trials by week 36–54.33,34 CONCLUSIONS

Biologics represent a new and potent therapeutic strategy that enables optimization of therapeutic interventions in IBD. The clinical use and efficacy profiles of the several biologics that inhibit the proinflammatory activity of TNF may be explained by their mechanism of action. In patients with IBD, inflammation is associated with the TNF-a and interferon-g pathways. In addition, inhibition of chemokine activation through direct suppression of chemotaxis and chemokinesis are of paramount importance. We suggest monitoring the Ctrough levels of these biologic therapies to ensure continued therapy efficacy and their safety. An alternative way of measuring the efficacy of the response of these products in a noninvasive manner is to measure activity in the serum of TNF-a (for anti-TNF antibodies), interleukins 12 and 23 (for anti-interleukins antibody), as well as that of cellular adhesion molecules (for anticellular adhesion molecule products). Serum TNF-a levels will reflect the inflammatory status of the organism at a certain point in time. It is important that the immune balance to be maintained to avoid infections and to permit immune system functionality. Moreover, therapeutic drug monitoring is essential for anti-integrin inhibitors to avoid serious adverse effects. Collaboration between a gastroenterologist and a special laboratory medicine professional might affect clinical practice in the treatment of CD and UC. Because patients with IBD are the beneficiaries of the therapy, further collaboration between the health professional team and the patients is advisable.

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REFERENCES

1. Neuman MG, Nanau RM. Inflammatory bowel disease: role of diet, microbiota, life style. Transl Res 2012;160:29–44. 2. Nanau RM, Neuman MG. Metabolome and inflammasome in inflammatory bowel disease. Transl Res 2012;160:1–28. 3. Neuman MG, Nanau RM. Single-nucleotide polymorphisms in inflammatory bowel disease. Transl Res 2012;160:45–64. 4. Barreiro O, Sanchez-Madrid F. Molecular basis of leukocyte– endothelium interactions during the inflammatory response. Rev Esp Cardiol 2009;62:552–62. 5. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009; 330:864–75. 6. REMICADE (infliximab). Highlights of prescribing information. 2013. Available at: http://www.remicade.com/shared/ product/remicade/prescribing-information.pdf. 7. HUMIRA (adalimumab). Highlights of prescribing information. 2013. Available at: http://www.rxabbvie.com/pdf/humira.pdf. 8. CIMZIA (certolizumab pegol). Highlights of prescribing information. 2012. Available at: http://www.cimzia.com/pdf/ Prescribing_Information.pdf. 9. SIMPONI (golimumab). Highlights of prescribing information. 2013. Available at: http://www.simponi.com/sites/default/files/ pdf/prescribing-information.pdf. 10. TYSABRI (natalizumab). Highlights of prescribing information. 2013. Available at: http://www.tysabri.com/pdfs/I61061-13_PI. pdf. 11. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710. 12. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21. 13. STELARA (ustekinumab). Highlights of prescribing information. 2013. Available at: http://www.stelarainfo.com/pdf/ PrescribingInformation.pdf. 14. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. 15. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. 16. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-tosevere Crohn’s disease in children. Gastroenterology 2007; 132:863–73. 17. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130: 323–33. 18. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232–9. 19. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146: 829–38. 20. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132: 52–65.

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Cohen et al

21. Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 2012; 142:1102–11. 22. Watanabe M, Hibi T, Lomax KG, et al. Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn’s disease. J Crohns Colitis 2012;6:160–73. 23. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357: 228–38. 24. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239–50. 25. Lichtenstein GR, Thomsen OØ, Schreiber S, et al. Continuous therapy with certolizumab pegol maintains remission of patients with Crohn’s disease for up to 18 months. Clin Gastroenterol Hepatol 2010;8:600–9. 26. Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, Bloomfield R, Lichtenstein GR. Reinduction with certolizumab pegol in patients with relapsed Crohn’s disease: results from the PRECiSE 4 Study. Clin Gastroenterol Hepatol 2010;8: 696–702. 27. Gordon FH, Lai CW, Hamilton MI, et al. A randomized placebocontrolled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease. Gastroenterology 2001;121: 268–74. 28. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32. 29. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–25. 30. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterology 2007;132:1672–83. 31. Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis 2007;13:2–11. 32. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol 2008;6: 1370–7. 33. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008;135:1130–41. 34. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519–28. 35. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. 36. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011;60:780–7. 37. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142:257–65. 38. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146:85–95.


39. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146:96–109. 40. Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 2005;352:2499–507. 41. Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis 2012;18:1470–9. 42. Zorzi F, Zuzzi S, Onali S, et al. Efficacy and safety of infliximab and adalimumab in Crohn’s disease: a single centre study. Aliment Pharmacol Ther 2012;35:1397–407. 43. Russo EA, Iacucci M, Lindsay JO, et al. Survey on the use of adalimumab as maintenance therapy in Crohn’s disease in England and Ireland. Eur J Gastroenterol Hepatol 2010;22: 334–9. 44. Nichita C, Stelle M, Vavricka S, et al. Clinical experience with adalimumab in a multicenter Swiss cohort of patients with Crohn’s disease. Digestion 2010;81:78–85. 45. Swoger JM, Loftus EV Jr, Tremaine WJ, et al. Adalimumab for Crohn’s disease in clinical practice at Mayo Clinic: the first 118 patients. Inflamm Bowel Dis 2010;16:1912–21. 46. Russell RK, Wilson ML, Loganathan S, et al. A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther 2011; 33:946–53. 47. Sprakes MB, Hamlin PJ, Warren L, Greer D, Ford AC. Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn’s disease: a single centre experience. J Crohns Colitis 2011;5:324–31. 48. Panaccione R, Loftus EV Jr, Binion D, et al. Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn’s disease: results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn’s DiseaSe (ACCESS) trial. Can J Gastroenterol 2011;25:419–25. 49. Barreiro-de-Acosta M, Lorenzo A, Domınguez-Mu~noz JE. Efficacy of adalimumab for the treatment of extraintestinal manifestations of Crohn’s disease. Rev Esp Enferm Dig 2012;104: 468–72. 50. Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology 2012;143:365–74. 51. L€ofberg R, Louis EV, Reinisch W, et al. Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn’s disease: results from CARE. Inflamm Bowel Dis 2012;18:1–9. 52. Baert F, Glorieus E, Reenaers C, et al. Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn’s patients. J Crohns Colitis 2013;7: 154–60. 53. Schoepfer AM, Vavricka SR, Binek J, et al. Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohn’s disease population: results of the FACTS survey. Inflamm Bowel Dis 2010;16:933–8. 54. Vavricka SR, Schoepfer AM, Bansky G, et al. Efficacy and safety of certolizumab pegol in an unselected Crohn’s disease population: 26-week data of the FACTS II survey. Inflamm Bowel Dis 2011;17:1530–9. 55. Hebuterne X, Lemann M, Bouhnik Y, et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn’s disease following treatment with certolizumab pegol. Gut 2013;62:201–8.


56. Parikh A, Fox I, Leach T, et al. Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:1691–9. 57. Hyams JS, Lerer T, Griffiths A, et al. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol 2010;105:1430–6. 58. Oussalah A, Evesque L, Laharie D, et al. A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization. Am J Gastroenterol 2010;105:2617–25. 59. Seow CH, Newman A, Irwin SP, et al. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49–54. 60. Taxonera C, Estelles J, Fernandez-Blanco I, et al. Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab. Aliment Pharmacol Ther 2011;33:340–8. 61. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10: 391–3. 62. H€am€al€ainen A, Sipponen T, Kolho KL. Serum infliximab concentrations in pediatric inflammatory bowel disease. Scand J Gastroenterol 2013;48:35–41. 63. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit 2008;30:523–9. 64. Smith LS, Nelson M, Dolder CR. Certolizumab pegol: a TNF-{alpha} antagonist for the treatment of moderate-tosevere Crohn’s disease. Ann Pharmacother 2010;44: 333–42. 65. Ling J, Lyn S, Xu Z, et al. Lack of racial differences in the pharmacokinetics of subcutaneous golimumab in healthy Japanese and Caucasian male subjects. J Clin Pharmacol 2010;50: 792–802. 66. Zhuang Y, Lyn S, Lv Y, et al. Pharmacokinetics and safety of golimumab in healthy Chinese subjects following a single subcutaneous administration in a randomized phase I trial. Clin Drug Invest 2013;33:795–800. 67. Zhu Y, Wang Q, Frederick B, et al. Comparison of the pharmacokinetics of subcutaneous ustekinumab between Chinese and non-Chinese healthy male subjects across two phase 1 studies. Clin Drug Invest 2013;33:291–301. 68. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: REACH open-label extension. Curr Med Res Opin 2011;27:651–62. 69. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–5. 70. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn’s disease in the SONIC trial. Gut 2013;63:88–95. 71. Reinisch W, Sandborn WJ, Panaccione R, et al. 52-Week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. Inflamm Bowel Dis 2013;19: 1700–9. 72. Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease. Aliment Pharmacol Ther 2010;31:1296–309.

Cohen et al

23

73. Kamm MA, Hanauer SB, Panaccione R, et al. Adalimumab sustains steroid-free remission after 3 years of therapy for Crohn’s disease. Aliment Pharmacol Ther 2011;34:306–17. 74. Rismo R, Olsen T, Ciu G, et al. The effect of adalimumab for induction of endoscopic healing and normalization of mucosal cytokine gene expression in Crohn’s disease. Scand J Gastroenterol 2012;47:1200–10. 75. Chaparro M, Panes J, Garcıa V, et al. Long-term durability of response to adalimumab in Crohn’s disease. Inflamm Bowel Dis 2012;18:685–90. 76. Schreiber S, Reinisch W, Colombel JF, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohns Colitis 2013;7:213–21. 77. Colombel JF, Sandborn WJ, Allez M, et al. Association between plasma concentrations of certolizumab pegol and endoscopic outcomes of patients with Crohn’s disease. Clin Gastroenterol Hepatol 2013. http://dx.doi.org/10.1016/j.cgh.2013.10.025. 78. Gustavsson A, J€arnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis: 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther 2010;32:984–9. 79. Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT1 and -2 extension studies. Inflamm Bowel Dis 2012;18: 201–11. 80. Sprakes MB, Ford AC, Warren L, Greer D, Hamlin J. Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn’s disease: a large single centre experience. J Crohns Colitis 2012;6:143–53. 81. J€arnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128:1805–11. 82. Sandborn WJ, Colombel JF, D’Haens G, et al. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther 2013;37:204–13. 83. Chiu YL, Rubin DT, Vermeire S, et al. Serum adalimumab concentration and clinical remission in patients with Crohn’s disease. Inflamm Bowel Dis 2013;19:1112–22. 84. Lichtiger S, Binion DG, Wolf DC, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy. Aliment Pharmacol Ther 2010;32:1228–39. 85. Gies N, Kroeker KI, Wong K, Fedorak RN. Treatment of ulcerative colitis with adalimumab or infliximab: long-term follow-up of a single-centre cohort. Aliment Pharmacol Ther 2010;32: 522–8. 86. Feagan B, Rutgeerts P, Sands B, et al. Induction therapy for ulcerative colitis: results of GEMINI I, a randomized, placebocontrolled, double-blind, multicenter phase 3 trial. Gastroenterology 2012;142:S160–1. 87. Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10:1079–87. 88. Bendtzen K, Ainsworth M, Steenholdt C, Thomsen OØ, Brynskov J. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies. Scand J Gastroenterol 2009;44:774–81.

24


Cohen et al

89. Afif W, Leighton JA, Hanauer SB, et al. Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab. Inflamm Bowel Dis 2009;15:1302–7. 90. Khanna R, Sattin BD, Afif W, et al. Review article: a clinician’s guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther 2013;38:447–59. 91. Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91:635–46. 92. Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 2013;108:40–8. 93. Atzeni F, Talotta R, Salaffi F, et al. Immunogenicity and autoimmunity during anti-TNF therapy. Autoimmun Rev 2013;12: 703–8. 94. Ben-Horin S, Yavzori M, Katz L, et al. The immunogenic part of infliximab is the F(ab0 )2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut 2011;60:41–8. 95. Imaeda H, Andoh A, Fujiyama Y. Development of a new immunoassay for the accurate determination of anti-infliximab antibodies in inflammatory bowel disease. J Gastroenterol 2012; 47:136–43. 96. Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients

97.

98.

99.

100.

101.

102.

103.

with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:1199–206. Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248–54. Kong JY, Bundell C, Pawlik J, Hollingsworth P, Forbes G. Low trough serum infliximab and antibodies to infliximab in smokers. Inflamm Bowel Dis 2013;19:E35–6. Moon CM, Park DI, Kim ER, et al. Clinical features and predictors of clinical outcomes in Korean patients with Crohn’s disease: a KASID multicenter study. J Gastroenterol Hepatol 2014;29:74–82. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009; 137:1628–40. Wang SL, Hauenstein S, Ohrmund L, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. J Pharm Biomed Anal 2013;78-79:39–44. Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014;12:80–4. Ferrante M, Vermeire S, Rutgeerts P. Certolizumab pegol in the treatment of Crohn’s disease. Expert Opin Biol Ther 2013;13: 595–605.

Biologic concentration testing in inflammatory bowel disease.

Advances in Therapeutic Drug Monitoring of Biologic Therapies in Inflammatory Bowel Disease: 2015 in Review.

Optimizing the Use of Biologic Therapies in the Management of Inflammatory Bowel Disease.

Public versus Private Drug Insurance and Outcomes of Patients Requiring Biologic Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease surgery in the biologic era.

Designing biologic selectivity for inflammatory bowel disease--role of vedolizumab.

Review article: anti-adhesion therapies for inflammatory bowel disease.

Inflammatory bowel disease therapies discontinued between 2009 and 2014.

Integrative Therapies and Pediatric Inflammatory Bowel Disease: The Current Evidence.

New and emerging therapies for inflammatory bowel disease.

Biologic targeting in the treatment of inflammatory bowel diseases [Retraction].

Mucosal healing in the era of biologic agents in treatment of inflammatory bowel disease.

What to Do When Biologic Agents Are Not Working in Inflammatory Bowel Disease Patients.

Increased Risk of Venous Thromboembolic Events With Corticosteroid Versus Biologic Therapy for Inflammatory Bowel Disease.

Legionellosis and biologic therapies.

Cytokines in inflammatory bowel disease.

Inflammatory bowel disease in Asia.

Inflammatory Bowel Disease.

Inflammatory bowel disease (1)

Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies.

Inflammatory Bowel Disease in Women.

Hyposplenism in inflammatory bowel disease.

Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects.

Inflammatory bowel disease: pathogenesis.