Scandinavian Journal of Gastroenterology. 2013; 48: 35–41

ORIGINAL ARTICLE

Serum infliximab concentrations in pediatric inflammatorybowel disease

ANSSI HÄMÄLÄINEN1, TAINA SIPPONEN2 & KAIJA-LEENA KOLHO1

1Children�s Hospital, Helsinki University Central Hospital, Helsinki, Finland, and 2Department of Medicine, Division ofGastroenterology, Helsinki University Central Hospital, Helsinki, Finland

AbstractObjective. To study serum infliximab (s-IFX) levels in pediatric patients with inflammatory bowel disease (IBD). Subjectsand methods. s-IFX trough levels were measured in a total of 133 blood samples of 37 pediatric IBD patients (Crohn’sdisease, 23): 48 during the induction phase (weeks 2 and 6) and 85 during maintenance treatment. Antibodies to infliximab(ATI) were determined in 93 samples (30 patients). s-IFX values were related to fecal calprotectin (FC) and serum markers ofinflammation.Results.During induction (5 mg/kg) andmaintenance therapy, the median s-IFX levels were 17.6 mg/ml (range0–48 mg/ml) and 3.55 mg/ml (range 0–40 mg/ml), respectively. The IFX levels were similar in ulcerative colitis and Crohn’sdisease (e.g. during maintenance median 3.2 vs. 2.8 mg/ml, p = 0.718), thus the data are pooled. During induction, the s-IFXlevel was associated with the total dose of IFX, that is, young children with lower body weight had lower levels (p < 0.001 atweek 2 and p < 0.05 at week 6). Shorter administration interval resulted in higher trough levels (p < 0.005). All samples withundetectable s-IFX (6.8%) levels presented ATI. High inflammation (FC >1000 mg/g) during induction was associated withlower s-IFX levels (median 4.0 mg/ml, range 0.47–25 compared to median 20 mg/ml, range 0–48 when FC <1000 mg/g,p < 0.005). There was no significant association between the ESR or values of C-reactive protein and s-IFX levels duringinduction. Conclusions. In pediatric IBD, lower body weight and higher level of intestinal inflammation are associated tos-IFX levels during induction but relation to therapeutic response is unclear.

Key Words: Crohn’s disease, fecal markers, therapy, TNF-a antagonist, trough levels, ulcerative colitis

Introduction

As in adults, infliximab (IFX), chimeric monoclonalantibody (IgG1) against TNF- is effective in childrenwith moderate to severe Crohn’s disease in inducingand maintaining remission [1,2]. Recently, the effec-tiveness of IFX in severe ulcerative colitis (UC) hasbeen demonstrated in pediatric patients [3–6]. Thus,the use of IFX in pediatric inflammatory bowel dis-ease (IBD) is likely to increase further in the future.In IBD, TNF-a antagonist agents, though efficient,

often lose their therapeutic effect for yet unknownreasons [7]. In pediatric Crohn’s disease, almost everyother of the primary respondents will need dose esca-lation within the first year of therapy [8–10]. So far, the

therapeutic effect of IFX cannot be foreseen and,accordingly, the reasons leading to a loss of therapeuticresponse are incompletely understood. The pharmaco-kinetics of IFX has recently been shown to be compa-rable between adult and pediatric patients, relating toweight instead of age [11]. There is, however, so farnoevidence that individualvariation inpharmacokineticproperties [11–13] is a causative factor for variation intherapeutic responses. At present, the mechanism forthe loss of response to TNF-a-antagonist has not beenfully explored and may include the formation of anti-bodies to IFX (ATI) [14,15].Measurement of serum IFX (s-IFX) levels is of

interest as a possible means to predict the courseof biological treatment in individual patients and to

Correspondence: Kaija-Leena Kolho,MD PhD, Children�s Hospital, University of Helsinki, Box 281, FIN-00029HUS,Helsinki, Finland. Tel: +358 9 471 74787.Fax: +358 9 471 75299. E-mail: kaija-leena.kolho@helsinki.fi

(Received 11 September 2012; revised 14 October 2012; accepted 15 October 2012)

ISSN 0036-5521 print/ISSN 1502-7708 online � 2013 Informa HealthcareDOI: 10.3109/00365521.2012.741619

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optimize dose intensity. Several publications haveshown that in adult patients with Crohn’s diseaseand UC low s-IFX levels are associated with a lossof response to IFX treatment, while the oppositeseems to be true for a maintained response [16,17].In adults, patients with detectable s-IFX have bettermaintained remission as well as lower values ofC-reactive protein and have achieved significantendoscopic improvement more often than patientswith undetectable s-IFX. However, some studieshave also suggested that regain of a lost response totreatment may occur independent of serum concen-trations [18]. Yet, there are no uniform criteria todetermine whether to increase the dose or shorten theinterval of administration in pediatric patients.Non-respondents to IFX had lower values of s-IFX

and higher levels of ATI than respondents [16,17].Notably, when the commercially available assaysare used, ATI can only be detected reliably (due toantigen binding) when the simultaneous s-IFX is low.Concomitant immunosuppression seems to lower thefrequency of ATI in on-demand IFX therapy [19],but the effect is debatable in scheduled therapy [16].The presence of ATI is associated with a threefoldincrease in clearance of IFX [12]. Currently, theimpact of ATI measurement for clinical decisionmaking is not that clear and awaits prospectivestudies [15,20].In pediatric patients, TNF–antagonist agents have

emerged in the therapy of moderate to severe IBD notresponding to conventional therapies [1–4,9]. Thereare limited data on the performance of s-IFX and ATIlevel measurements in pediatric patients with IBD.We aimed to assess the performance of s-IFX andATI in pediatric IBD patients during IFX therapy.

Subjects and methods

Thirty-seven pediatric patients with IBD on IFX ther-apy in the Children’s Hospital, Helsinki, Finland con-sented to the study and s-IFX was tested in availableserum samples (Table I). Remicade� (Janssen Biotech,Inc/Schering-Plough, EU) infusions were adminis-tered on weeks 0, 2 and 6 at induction with a doseof 5 mg/kg followed by 8-week dosing intervalsduring maintenance. Patients were naïve to previousTNF-blocking therapies.Serum samples were taken between April 2008 and

April 2010. IFX doses were recorded along withserum markers of inflammation (erythrocyte sedi-mentation rate, ESR, and C-reactive protein) andfecal calprotectin (FC) and concomitant medication.FC was measured in a routine clinical laboratoryby a quantitative enzyme immunoassay (PhiCalTest, Calpro AS, Oslo, Norway), and the values

quoted as normal were <100 mg/g and the valuesquite high >1000 mg/g of stool [21,22].Serum samples were tested for IFX levels and ATI in

a commercial laboratory, Sanquin Biologicals, theNetherlands, using validated immunoassays for bothmeasurements. The results of the s-IFX and ATI levelswere not available at the timewhen clinical decisions onthe dosing or outcome of the therapy were made.

Ethics

The patients involved in this study participated in astudy on TNF-a-antagonist treatment approved bythe Ethics Committee of the Helsinki UniversityCentral Hospital. The patients/their guardians signedan informed consent form.

Statistical analyses

Statistical analysis for the effect of IFX dose elevationfrom 5 mg/kg to 10 mg/kg and of shortening theadministration interval on s-IFX levels was performedby the Mann–Whitney U test and linear regressionanalysis, respectively. For correlation between s-IFXconcentration and FC, ESR and C-reactive protein,linear regression analysis and Kruskal–Wallis test wereused, respectively. GraphPad Prism� Version 5.0c wasused for the analyses. Significance was set at p < 0.05.

Results

The total number of s-IFX concentration measure-ments obtained from the 37 patients (Table I) was 133.

Table I. Background characteristics of the 37 pediatric patientstreated with IFX infusions.

No. of patients, total 37Gender, Male 18AgeMedian, years 14 (range 5.6–18)WeightMedian, kg 43.5 (range 19.6–67.1)DiagnosesCrohn’s disease 23Ileocolonic 14Colonic 3Ileal 5Perianal 1UC 14Extensive colitis 13Left-sided 1Disease durationMedian, years 2.1 (range 0.1–8.7)Concomitant immunosuppressionat induction (no. of patients)Thiopurines 14Cyclosporine 3Glucocorticoids 14

36 A. Hämäläinen et al.

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There were 1 to 10 samples per patient (median 3).During the study period, 11 patients had samples onlyduring induction regimen, 12 patients only duringmaintenance and 14 patients had samples duringboth regimens. Thus, the total number of patients ininduction was 25 and in maintenance 26. Backgroundcharacteristics of the patients are shown in Table I.The IFX levels were similar in UC and Crohn’s disease(e.g. during maintenance median 3.2 vs. 2.8 mg/ml,p = 0.718), thus the data are pooled.During induction, the median s-IFX level was

17.6 mg/ml (range 0–48 mg/ml; 45 samples available).At week 2, the s-IFX level was associated with the

total amount of IFX at first infusion (given 5 mg/kg),that is, young children with lower body weight hadsignificantly lower levels (p < 0.001; Figure 1). Atweek 6, this association was less clear (p = 0.0445;Figure 1). One patient had an undetectable levelduring induction and another a very low level.During maintenance, the median s-IFX level was

3.55 mg/ml with a median interval between infusions6.6 weeks (range 2.7–12.1 weeks). An example ofindividual variation is shown in Figure 2. Further-more, s-IFX trough levels were comparable betweendoses 5 and 10 mg/kg (p = 0.578; Figure 3). Doseintensification by shortening intervals between infu-sions in maintenance therapy (in 12 patients) seemedto mildly elevate s-IFX levels respective to timeelapsed since the previous infusion (p = 0.0002 andp = 0.0013 for 5 and 10 mg/kg, respectively). Sub-group analyses using only the first sample per subjectyielded similar results in all analyses, indicating lowrisk for repeated measures bias (data not shown).In three patients (8.1%), the level of s-IFX was

undetectable in a total of nine samples (6.8% of alltested samples); all except one were taken duringmaintenance therapy with a dose interval from sixto eight weeks (see also below). The preceding dose ofIFX had been 5 mg/kg in five samples and 10 mg/kg infour samples (Table II).Of the total 133 samples, 93 were assayed for ATI,

and these were detected in 18 out of 93 (19%) but inonly 5 out of 28 (18%) patients (Table II). Of theseATI positive samples, 9 out of 18 (50%) had mea-surable s-IFX levels. The highest level of s-IFXwith ATI was 2.2 mg/ml, possibly reflecting the detec-tion limit for ATI in this commercial assay (the exactinformation not available). Among samples with

3020100

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400

6040200

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Figure 1. The s-IFX levels related to given dose during induction ofIFX therapy in pediatric patients with IBD. At week 2, the s-IFXlevel was associated with the total amount of IFX at first infusion(given 5 mg/kg), that is, young children with lower body weight hadsignificantly lower levels (p = 0.0055, linear regression analysis). Atweek 6, this association was less clear (p = 0.0445, linear regressionanalysis).

*

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Figure 2. The s-IFX trough levels measured by the time of nextinfusion in three pediatric patients during their first year of therapy.*dose 10 mg/kg.

Serum Infliximab in Pediatric IBD 37

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measurable s-IFX levels below this threshold, 33%presented ATI. Three patients were repeatedly posi-tive for ATI, showing a variation in their ATI levels(from 32 to 860; Table II), and all of them hadconcomitant immunosuppression during inductionof IFX. In these particular patients, the presenceof ATI seemed to associate with poor outcome ofIFX therapy.

FC was available in 112 occasions of s-IFXmeasurements. Of these, 33 occasions were duringinduction and higher s-IFX levels were associatedwith lower FC levels by induction (p < 0.005; median

s-IFX 20 mg/ml, range 0–48 when FC <1000 mg/g(median 115 mg/g) and 4.0 mg/ml, range 0.47–25when FC >1000 mg/g (median 1645 mg/g); Figure 4),but there was no such association later on (p = 0.276).The cut-off defining higher levels here was FC1000 mg/g [21–23].There was no significant association between the

ESR and s-IFX levels during induction (n = 43;p = 0.213). Values of C-reactive protein were belowthe limit for a raised value in most patients, andassociation to IFX could not be assessed (data notshown).

Discussion

IBD is a disease becoming increasingly prevalent bothin adults and children [24,25]. Ranging from mode-rate to severe disease, it frequently necessitates treat-ment with efficient immunomodulatory agents, suchas IFX, a chimeric antibody antagonistic to TNF-a.Monitoring IFX levels in serum is considered apromising means to predict the course of treatmentand to allow for optimization of dose intensity. To thebest of our knowledge, this is one of the first studiesreporting s-IFX levels in pediatric IBD patientsduring IFX therapy. No similar results exist for juve-nile idiopathic arthritis, either. Our findings suggestthat in pediatric IBD lower body weight and higherlevel of intestinal inflammation are associated withs-IFX levels during induction. The relation of s-IFXto therapeutic response, however, is unclear.As expected, median s-IFX levels were significantly

higher during induction than during maintenance

5 mg/kg10 mg/kg

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40

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Figure 3. The s-IFX trough levels in pediatric patients with IBDduring maintenance therapy. Trough levels were comparablebetween doses 5 and 10 mg/kg (p = 0.578). IFX dose 5 mg/kg (.)and 10 mg/kg (D).

Table II. Trough level of IFX in s-IFX in samples with ATI in pediatric patients with IBD.

No. ofpatient Diagnosis

ATI titreAU/ml S-IFX mg/ml

Weeks fromprevious infusion

Previous doseof IFX mg/kg

Outcome of therapeuticresponse to IFX

1. Crohn 290 <0.002 4 (induction) 5120 <0.002 8 590 <0.002 7 532 0.019 3 5110 0.002 5 5 Loss of response

2. Crohn 450 <0.002 8 10460 <0.002 8 10260 0.003 6 10290 <0.002 8 5 Discontinuation due

to allergic reaction3. Crohn 50 0.026 8 5

61 0.021 4 5400 <0.002 4 10660 <0.002 6 5450 0.003 6 560 0.075 4 5860 <0.002 6 10 Loss of response

4. Crohn 16 2.20 4 (induction) 5 Good response5. UC 36 0.175 4 (induction) 5 Poor response

38 A. Hämäläinen et al.

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therapy [26], but the range of values was basically thesame for both regimes. This reflects shorter intervalsin administration and suggests interindividual varia-tion. In young children with lower body weight, theinduction dose of 5 mg/kg resulted in significantlylower levels of IFX by week 2, but by week 6 thedifference was less marked. So far, there is no evi-dence of clinically relevant accumulation of IFX [11],but whether the elimination half-life is comparable inyoung children and adolescents is not known. To ourknowledge, one published study exists describing thepharmacokinetics of IFX in pediatric patients. Theauthors concluded that there are no major differencesbetween pediatric patients, but that the assessmentwas based on a median body weight of 42 kg [13],which is significantly higher than the body weight ofthe youngest patients in our study.During maintenance therapy, raising the dose from

5 to 10 mg/kg did not have a significant effect ons-IFX levels; shortening the administration intervalwas a more successful method in this respect. Previ-ously, it has been shown in adult IBD that detectablelevels of s-IFX correlate with sustained response totreatment with IFX, while the contrary is true fornon-detectable levels [16,17,27]. Here, undetectableIFX levels were rare, seen only in approximately8% of the patients and mostly during maintenance.For evaluation of response to treatment, FC

and blood inflammatory markers were used here.

However, FC has been shown to be more reliablemarker for intestinal inflammation than serum mar-kers of inflammation and clinical indices [28–30]and has recently also been shown to rapidly declinewithin few weeks after introduction of the IFXtherapy [23]. Interestingly, during induction, thes-IFX levels were higher in patients with lower FClevel when ESR levels were comparable. Whetherthis can be associated with better outcomes isunclear, as there were too few individual follow-upsamples. Furthermore, there was no such associationlater on when s-IFX levels did not seem to correlatewith FC. Also in adults the association of s-IFX toFC is inadequately studied.Ambiguous results of the impact of ATI in ther-

apeutic response to IFX have been obtained inadults, though these have been associated with lossof treatment response, shorter response duration,and risk of infusion reactions [16,17,20,27,31–33].In our patients, ATI were detected in only fivepatients, and thus the impact of the presence ofATI to the outcome of therapy is inconclusive.Notably, the patients with ATI were on concomitantimmunosuppression. However, based on this limitednumber of patients, repeatedly high titres of ATIcould be associated with low s-IFX levels andpoor response to IFX therapy also in pediatricpatients. Due to the low number of patients,we did not study switching to another TNFa-antagonist. Our samples were commercially analyzedfor ATI, the major limitation being, according tothe Sanquin laboratories, interference by high con-centrations of IFX when detecting ATI. Therefore,s-IFX being high, ATI cannot be detected reliablyand the true proportion of patients with ATI [14,15]remains unclear.The strength of this study is the relatively high

number of pediatric serum samples and FC valuesavailable in most occasions. The clinicians did notknow the results of the s-IFX and ATI measurementswhen they adjusted the dose or infusion interval. As alimitation, we tested all available samples, and thusthe number of samples per patient varied in theretrospective set-up. Furthermore, as in many pedi-atric studies, endoscopies were not performed duringroutine follow-up nor would this have been ethical atall time-points.In conclusion, in pediatric patients with IBD, active

inflammation reflected in higher FC levels mayrelate to lower s-IFX levels during induction therapy.During maintenance, the more effective strategy toincrease s-IFX trough levels seems to be by shorteningadministration intervals than by increasing the dose.This does not necessarily, however, give bettertherapeutic effect.

IFX

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20

40

60

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Good

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Figure 4. The s-IFX trough levels in pediatric patients with IBDrelated to the level of intestinal inflammation during induction ofthe IFX therapy. The figure depicts patients showing either goodresponse, that is, low level of inflammation (FC <1000 mg/g, median115 mg/g) or inadequate response, that is, high level of inflammation(FC >1000 mg/g; median 1645 mg/g), p < 0.005 between groups(Mann–Whitney U test).

Serum Infliximab in Pediatric IBD 39

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Acknowledgments

The authors thankMsAnneNikkonen for her excellentassistance in gathering the patient data.

Declaration of interest: Financial support: FinnishPediatric Research Foundation Helsinki (KLK), andUniversity Central Hospital Research Fund (KLK).There is no conflict of financial interests.

References

[1] Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A,Johanns J, et al. Induction and maintenance infliximab ther-apy for the treatment of moderate-to-severe Crohn’s diseasein children. Gastroenterology 2007;132:863–73.

[2] Hyams J, Walters TD, Crandall W, Kugathasan S,Griffiths A, BlankM, et al. Safety and efficacy of maintenanceinfliximab therapy for moderate-to-severe Crohn’s disease inchildren: REACH open-label extension. Curr Med Res Opin2011;27:651–62.

[3] Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M.Infliximab efficacy in pediatric ulcerative colitis. InflammBowel Dis 2005;11:213–18.

[4] McGinnis JK, Murray KF. Infliximab for ulcerative colitisin children and adolescents. J Clin Gastroenterol 2008;42:875–9.

[5] Turner D, Mack D, Leleiko N, Walters TD, Uusoe K,Leach ST, et al. Severe pediatric ulcerative colitis:a prospective multicenter study of outcomes and predictorsof response. Gastroenterology 2010;138:2282–91.

[6] Hyams JS, Lerer T, Griffiths A, Pfefferkorn M, Stephens M,Evans J, et al. Outcome following infliximab therapy inchildren with ulcerative colitis. Am J Gastroenterol 2010;105:1430–6.

[7] Yanai H, Hanauer SB. Assessing response and loss ofresponse to biological therapies in IBD. Am J Gastroenterol2011;106:685–98.

[8] de Ridder L, Rings EH, Damen GM, Kneepkens CM,Schweizer JJ, Kokke FT, et al. Infliximab dependency inpediatric Crohn’s disease: long-term follow-up of an unse-lected cohort. Inflamm Bowel Dis 2008;14:353–8.

[9] Hyams JS, Lerer T, Griffiths A, Pfefferkorn M,Kugathasan S, Evans J, et al. Long-term outcome of main-tenance infliximab therapy in children with Crohn’s disease.Inflamm Bowel Dis 2009;15:816–22.

[10] De Bie CI, Hummel TZ, Kindermann A, Kokke FT,Damen GM, Kneepkens CM, et al. The duration ofeffect of infliximab maintenance treatment in pae-diatric Crohn’s disease. Aliment Pharmacol Ther 2011;33:243–50.

[11] Klotz U, Teml A, Schwab M. Clinical pharmacokinetics anduse of infliximab. Clin Pharmacokinet 2007;46:645–60.

[12] TernantD, Aubourg A,Magdelaine-BeuzelinC,DegenneD,Watier H, Picon L, et al. Infliximab pharmacokinetics ininflammatory bowel disease patients. Ther Drug Monit2008;30:523–52.

[13] Fasanmade AA, Adedokun OJ, Blank M, Zhou H,Davis HM. Pharmacokinetic properties of infliximab in chil-dren and adults with Crohn’s disease: a retrospective analysisof data from 2 phase III clinical trials. Clin Ther 2011;33:946–64.

[14] Colombel J-P, Feagan BG, Sandborn W, Van Assche G,Robinson AM. Therapeutic drug monitoring of biologics forinflammatory bowel disease. Inflamm Bowel Dis 2012;18:349–58.

[15] Chaparro M, Guerra I, Muñoz-Linares P, Gisbert JP. Sys-tematic review: antibodies and anti-TNF- levels in inflam-matory bowel disease. Aliment Pharmacol Ther 2012;35:971–86.

[16] Maser EA, Villela R, Silverberg MS, Greenberg GR. Asso-ciation of trough serum infliximab to clinical outcome afterscheduled maintenance treatment for Crohn’s disease. ClinGastroenterol Hepatol 2006;4:1248–54.

[17] Steenholdt C, Bendtzen K, Brynskov J, Thomsen OO,Ainsworth MA. Cut-off levels and diagnostic accuracy ofinfliximab trough levels and anti-infliximab antibodies inCrohn’s disease. Scand J Gastroenterol 2011;46:310–18.

[18] Pariente B, Pineton de Chambrun G, Krzysiek R,Desroches M, Louis G, De Cassan C, et al. Trough levelsand antibodies to infliximab may not predict response tointensification of infliximab therapy in patients with inflam-matory bowel disease. Inflamm Bowel Dis 2012;18:1199–206.

[19] Vermeire S, Noman M, Van Assche G, Baert F, D�Haens G,Rutgeerts P. Effectiveness of concomitant immunosuppres-sive therapy in suppressing the formation of antibodies toinfliximab in Crohn’s disease. Gut 2007;56:1126–31.

[20] Cassinotti A, Travis S. Incidence and clinical significance ofimmunogenicity to infliximab in Crohn’s disease: a criticalsystematic review. Inflamm Bowel Dis 2009;15:1264–75.

[21] Kolho KL, Raivio T, Lindahl H, Savilahti E. Fecal calpro-tectin remains high during glucocorticoid therapy in childrenwith inflammatory bowel disease. Scand J Gastroenterol2006;41:720–5.

[22] Sipponen T, Kolho K-L. Faecal calprotectin in children withclinically quiescent inflammatory bowel disease. Scand JGastroenterol 2010;45:872–7.

[23] Hämäläinen A, Sipponen T, Kolho KL. Infliximab in pedi-atric inflammatory bowel disease rapidly decreasesfecal calprotectin levels. World J Gastroenterol 2011;17:5166–71.

[24] Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M,Van Limbergen J, Griffiths AM. Epidemiology of pediatricinflammatory bowel disease: a systematic review of interna-tional trends. Inflamm Bowel Dis 2011;17:423–39.

[25] Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M,Chernoff G, et al. Increasing incidence and prevalence of theinflammatory bowel diseases with time, based on systematicreview. Gastroenterology 2012;142:46–54.

[26] Cornillie F, Shealy D, D�Haens G, Geboes K, Van Assche G,Ceuppens J, et al. Infliximab induces potent anti-inflammatoryand local immunomodulatory activity but no systemic immunesuppression in patients withCrohn’s disease. Aliment Pharma-col Ther 2001;15:463–73.

[27] Seow CH, Newman A, Irwin SP, Steinhart AH,Silverberg MS, Greenberg GR. Trough serum infliximab:a predictive factor of clinical outcome for infliximab treat-ment in acute ulcerative colitis. Gut 2010;59:49–54.

[28] Langhorst J, Elsenbruch S, Koelzer J, Rueffer A,Michalsen A, Dobos GJ. Noninvasive markers in the assess-ment of intestinal inflammation in inflammatory boweldiseases: performance of fecal lactoferrin, calprotectin, andPMN-elastase, CRP, and clinical indices. Am J Gastroen-terol 2008;103:162–9.

[29] Quail MA, Russell RK, Van Limbergen JE, Rogers P,Drummond HE, Wilson DC, et al. Fecal calprotectin

40 A. Hämäläinen et al.

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1/14

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complements routine laboratory investigations in diagnosingchildhood inflammatory bowel disease. Inflamm Bowel Dis2009;15:756–9.

[30] Henderson P, Casey A, Lawrence SJ, Kennedy NA,Kingstone K, Rogers P, et al. The diagnostic accuracy offecal calprotectin during the investigation of suspected pedi-atric inflammatory bowel disease. Am J Gastroenterol 2012;107:941–9.

[31] Afif W, Loftus EVJ, Faubion WA, Kane SV, Bruining DH,Hanson KA, et al. Clinical utility of measuring infliximab andhuman anti-chimeric antibody concentrations in patients

with inflammatory bowel disease. Am J Gastroenterol2010;105:1133–9.

[32] Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosisfactor-alpha binding capacity and anti-infliximab antibodiesmeasured by fluid-phase radioimmunoassays as predictorsof clinical efficacy of infliximab in Crohn’s disease. Am JGastroenterol 2008;103:944–8.

[33] Baert F, Noman M, Vermeire S, Van Assche G, D�Haens G,Carbonez A, et al. Influence of immunogenicity on thelong-term efficacy of infliximab in Crohn’s disease. N EnglJ Med 2003;348:601–8.

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