Abstract

Background

Infliximab (IFX) is effective in treating Crohn's disease (CD) and C-reactive protein (CRP) is a useful biomarker in assessing inflammatory activity.

Aim

Correlate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment.

Methods

Retrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug.

Results

Baseline CRP levels were higher in PNR compared with SR (26.2 mg/L vs 9.6 mg/L, p = 0.015) and RTA (26.2 mg/L vs 7.6 mg/L, p = 0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1 mg/L vs 7.6 mg/L p = 0.019) and PNR (3.1 mg/L vs 9.1 mg/L; p = 0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2 mg/L vs 0.6 mg/L p = 0.027).

Conclusion

CRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response.

Introduction

Inflammatory bowel disease (IBD) is an idiopathic, chronic process of the bowel associated with decreased quality of life and increased morbidity.1 It is believed to be the result of an imbalance between proinflammatory and anti-inflammatory mediators2 and tumor necrosis factor (TNF)-α is now known to play a pivotal role in the onset and perpetuation of the inflammation. Infliximab (IFX) is a chimeric IgG 1 monoclonal antibody with high specificity and affinity to TNF-α.38 Clinical benefit from IFX is reported in 60–70% of the patients in short and medium term,913 however, secondary loss of response is intrinsic to the use of therapeutic antibodies and up to 30–40% of patients who initially respond to IFX, lose response within the first year.1113

C-reactive protein (CRP), an acute phase reactant, is produced and released by hepatocytes in response to cytokine (interleukin-6, TNF-α and interleukin-1β) stimulation at the site of inflammation.14 CRP plays an important role as a noninvasive inflammatory marker in patients with IBD, however, there is remarkable heterogeneity in the CRP response between Crohn's disease (CD) and ulcerative colitis (UC). Whereas CD is associated with a strong CRP response, UC has only a modest to absent CRP response.1419 Besides that, in CD, a significant number of patients present with low CRP levels despite clinically active disease. So far, no clear cut-off values have been determined as predictive of remission/nonresponse/relapse. Different studies suggest that lower baseline CRP levels can predict nonresponse, as it may correspond to absence of inflammation. Increased CRP levels in CD have been associated with relapse. Once a wide range of CRP values are observed, with significant overlap between different degrees of severity, the dynamics of CRP evolution and the comparison of the CRP value with previous values in a given patient, might be more important than a particular cut off value for CRP.17,2026

Our aim is to correlate CRP levels before beginning of IFX, at week 14 and CRP delta between baseline and week 14 in patients that have primary nonresponse (PNR), sustained remission (SR) or response after therapeutic adjustment (RTA) within the first year of IFX treatment.

Material and methods

Retrospective study based on medical records from patients with CD undergoing treatment with IFX (followed at our institution) between January 2006 and February 2012. Diagnosis of CD was made by endoscopic, radiologic and histological criteria,27 and indication for IFX treatment was judged by senior IBD gastroenterologists taking into consideration clinical, biological, and endoscopic findings.

Our study was performed with 148 CD patients and their serum CRP was evaluated. Serial blood samples were taken before each IFX infusion, and CRP was measured as part of standard follow-up by using an enzyme-linked immunosorbent assay (Olympus CRPLatex Calibrator Normal Set®). A CRP level below 3 mg/L was considered normal. In total, there were available 1776 serial CRP measurements, with a median of 12 per patient. Week 14 was the time point selected to evaluate if the induction therapy was successful once it corresponds to the end of the induction and the beginning of maintenance treatment. All clinical data and CRP values were collected from the patients' records and were related to clinical outcome, namely relapse of disease activity and the need for therapy adjustment. Harvey–Bradshaw index (HBI) was used to assess patients' symptoms, being assessed by the senior IBD gastroenterologist at each clinic visit; those who scored 4 or less were considered to be in clinical remission and those who scored more to have clinical activity. All patients were submitted to colonoscopy in the three months previous to beginning of IFX treatment, with all patients having endoscopic activity, with ulcers. Other causes that could mimic disease activity, including infections (clostridium difficile, cytomegalovirus, bacterial, mycobacterium tuberculosis) were ruled out. Standard imaging with abdominal ultrasound or computed tomography was performed, whenever there was a suspicion of abscesses, perforating disease with phlegmone or any other complication. None of our patients had any of those complications. A protocol is followed before IFX beginning and during therapy, with patients starting IFX only after discussion between senior IBD gastroenterologists responsible for the IBD outpatient clinic. In all our patients, IFX was started due to the severity of luminal disease and not due to perianal disease or for prevention of post-operative recurrence.

All patients received a 5 mg/kg IFX infusion at baseline and then received subsequent infusions of 5 mg/kg at weeks two, six and then every 8 weeks. In case of loss of clinical response, optimization of anti-TNF treatment was always considered as primary intention (dose escalation to 10 mg/Kg or shortening infusion interval to every 6 weeks were made if patients remained symptomatic) and was a decision of the patient's gastroenterologist. Neither IFX trough levels nor IFX antibodies were available. Therapy adjustments were considered clinically successful if symptoms disappeared (HBI score ≤ 4) and if IFX could be continued thereafter without further adjustments (increase dose, shorten interval or addition of immunomodulators). PNR was defined as absence of symptomatic improvement and CRP persistently high (despite therapeutic adjustments); SR as symptomatic improvement for at least 1 year without need for any dose or interval adjustment or any other changes in therapy; RTA as analytic and clinical response after IFX dose modification and/or association of another drug (steroids, immunomodulators); short-term response (STR) as clinical improvement in those who have not yet completed one year of treatment. CRP delta was defined as the CRP variation between baseline and week 14 (i.e. week 14 CRP minus baseline CRP).

Statistics

All data were arranged, processed and analyzed with SPSS® v.18.0 data (Statistical Package for Social Sciences). Categorical variables were described through absolute and relative frequencies and continuous variables were described as mean and standard deviation, median, percentiles, minimum and maximum. Hypotheses were tested about the distribution of continuous variables with non-normal distribution, by using the nonparametric Mann–Whitney and Kruskal–Wallis tests, depending on the nature of the hypothesis. Model performances were assessed using the area under the ROC curve (ROC AUC). Logistic regression was used to determine the relationship between CRP delta and treatment failure regarding sustained response (adjusted to baseline CRP). For an effect size of 0.30 the sample power is around 80% for a confidence level of 95%. The effect size was used to calculate the power of the sample and was calculated using posthoc values. For that, average values of the variable of interest and of the different study groups were used. Software used was Gpower and family test T test, as well, as the test available — means: Wilcoxon–Mann–Whitney test (two groups). All hypotheses were tested at 5% level of significance.

Results

Population

Baseline demographic characteristics of all 148 patients with CD in treatment with IFX are summarized in Table 1. Most CD patients who started treatment with IFX had ileocolonic disease (39%), with non-stricturing, non-penetrating behavior (44%). IFX was started in all the patients due to severity of luminal disease, even in those with concomitant perianal disease. The primary indication for treatment was disease activity despite azathioprine full-dose treatment (mean dose of 2 mg/kg; thiopurine methyltransferase test was not available) (46% patients), followed by corticosteroid dependency (18% patients) and azathioprine intolerance (15% patients). Sixty-four percent of the patients have previously been treated with azathioprine and corticosteroids, and treatment was started as combination in 82% of the patients (Table 2).

In our study, 12 patients out of 148 had persistent low CRP levels despite having clinical and endoscopic activity. However, no correlation was found with age at diagnosis (p = 0.110), disease location (p = 0.561), disease behavior (p = 0.787) or response to IFX (p = 0.758).

Baseline CRP and week 14 CRP levels were not influenced by perianal disease (p = 0.622 and p = 0.797, respectively), disease location (p = 0.162 and p = 0.969, respectively) or disease behavior (p = 0.368 and p = 0.608, respectively).

Treatment response

Patients' response to IFX treatment is described in Fig. 1. Sixteen CD patients were responding to IFX but have not yet reached 1 year of treatment (short-term response). For long-term analysis, only patients on maintenance therapy for at least one year who were considered SR or those considered PNR or RTA were included. In CD, there was no significant association between IFX response and gender (p = 0.064) or age at diagnosis (p = 0.745) (Table 3). No significant association was found between location and response to IFX (p = 0.528), but patients with longer disease duration responded worse to IFX (either PNR or RTA) than those with shorter disease duration (p = 0.006) (Table 3).

Ileocolonic disease was not statistically significant associated with a further dose increase (p = 0.514) or shortening of frequency (p = 0.212) regarding other disease locations, as well as, combination treatment did not influence the need of dose adjustment (p = 0.799) nor the need of frequency adjustment (p = 0.498).

C-reactive protein levels and response

Baseline

The median baseline CRP value was 9.0 mg/L. Baseline CRP values were higher in PNR patients when compared to those with SR (26.2 mg/L vs 9.6 mg/L; p = 0.015) or RTA (26.2 mg/L vs 7.6 mg/L; p = 0.007) (Fig. 2). There was no statistical difference between the patients with SR and the patients with RTA (9.6 vs 7.6; p = 0.432). CRP values greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity (Fig. 3). The negative predictive value (NPV) was 93%.

Baseline CRP levels did not influence hospitalization (9 mg/L [0.1–125.0] vs 9 mg/L [0.6–200.2], p = 0.805).

Week 14

CRP values at week 14 were lower in patients with SR when compared to those with PNR (3.1 mg/L vs 9.1 mg/L; p = 0.013) or RTA (3.1 mg/L vs 7.6 mg/L; p = 0.019), while it did not differ between patients with PNR and RTA (9.1 mg/L vs 7.6 mg/L; p = 0.363) (Fig. 4).

Lower CRP levels at week 14 (< 3 mg/L) were associated with sustained response, e.g. 78% of patients with CRP levels < 3 mg/L at week 14 compared with 57% of patients with CRP levels > 3 mg/L achieved sustained response (p = 0.053) (Table 3). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity (Fig. 3). The NPV was 94%.

CRP was significantly lower at week 14 in patients on combination maintenance treatment (p = 0.031).

There was a trend to higher CRP levels at week 14 (4.7 mg/L [0.1–110.0] vs 3 mg/L [0.1–81.0], p = 0.079) predict hospitalization.

CRP delta

CRP delta between baseline and week 14 of treatment was higher in patients with SR than in those with RTA (5.2 mg/L vs 0.6 mg/L; p = 0.027), while there was no difference between PNR and SR (5.8 mg/L vs 5.2 mg/L) or PNR and RTA (5.8 mg/L vs 0.6 mg/L). The probability of RTA regarding SR decreases 0.914 for each increase of one delta unit [0.848–0.986], which means that the likelihood of SR regarding RTA increases with the increase of delta. This result is adjusted to the baseline CRP. It is possible to see that there is a linear correlation between baseline CRP and CRP delta, either in SR or in RTA, but with different Pearson's correlations (Fig. 5).

Considering a CRP level cut-off of 4.6 mg/dL at week 14 as predictor of non-response, a CRP delta lower than 3.1 predicts non-response with 67% sensitivity and 64% specificity.

Discussion

Our purpose was to explore the association between CRP levels and the clinical outcome of patients with CD treated with IFX, followed at a tertiary center. The applicability of clinical trials results to routine clinical practice has been frequently questioned28 and, herein, we have the opportunity to evaluate the results of current practice.

We would like to emphasize the importance of CRP levels at week 14, once lower CRP levels at this time were associated with sustained response in patients treated with IFX, independently of baseline CRP serum levels. This has already been showed in previous reports.11,29 In the study by Reinisch et al.,29 normalization of CRP at week 14 (< 5 mg/L) predicted a higher rate of response and remission during the first year. However, no optimal cut-off at week 14 has previously been established as predictive of nonresponse. Herein, we suggest that CRP levels higher than 4.6 mg/L might be predictive of nonresponse, with 67% sensitivity and 62% specificity. This is particularly useful, when considered together with CRP deltas between beginning of treatment and week 14, once higher deltas are predictive of sustained response in relation to those with need of therapeutic adjustment. CRP delta wasn't predictive of sustained response when compared with nonresponse, however, if we define a CRP level cut-off of 4.6 mg/dL at week 14 as predictor of non-response, CRP delta lower than 3.1 predict non-response with 67% sensitivity and 64% specificity. This highlights the need to combine CRP levels at week 14 with CRP delta. This way, patients with lower CRP values at week 14 and higher CRP variations are less likely to need further therapeutic adjustments. We selected week 14 for our analysis since this is when the efficacy of the induction phase is usually assessed and maintenance treatment starts.11 Similar results were achieved with Adalimumab (ADA), as shown by Kiss LS30 where lower CRP levels at week 12 (< 5 mg/L) were associated with a higher likelihood of clinical remission at one year of treatment.31 If CRP levels do not improve at week 14, a new assessment of the patient should be done,32 considering the need for therapeutic adjustment or a combination of another drug.

Previous studies14,29,32 suggest, in opposition to our results, that lower baseline CRP levels can predict nonresponse, as they may correspond to absence of inflammation and, thus, have no response to anti-TNF treatment. Cut-off levels in W. Reinisch29 and M. Jürgens32 were 7–25 mg/L [18.8 ± 24.1 mg/L] and 3 mg/L [IQR 1.5–35.3 mg/L], with higher values being associated with maintenance of response. E. Louis33 achieved similar results, with response rates being higher in patients with CRP levels higher than 5 mg/L [IQR 5–160 mg/L]. Similar results for response and remission were seen with ADA34 and Certolizumab35 (10 mg/L in both).

In SONIC trial, patients who had low CRP levels and no endoscopic lesions responded worse to treatment.36 Considering this, symptoms might be attributed to causes other than active CD. In our study, primary nonresponders had higher baseline CRP, with levels greater than 15 mg/L predicting nonresponse with 67% sensitivity and 65% specificity. There was no difference regarding IFX response, when a cut-off value of 3 mg/L was established (levels below 3 mg/L were considered normal). However, all our patients were submitted to an endoscopy in the three months previous to beginning of IFX treatment, which showed, in all of them, endoscopic activity, with ulcers. Previous studies25,26,37,38 depicted that higher CRP levels were associated with more severe disease. Because of their high molecular weight, monoclonal antibodies do not undergo renal elimination or metabolism by hepatic enzymes. The catabolism occurs within the cells of the reticuloendothelial system as the primary route of elimination.39 Disease severity may influence elimination of antibodies through reticuloendothelial system-mediated mechanisms.40 It has been shown that patients with elevated CRP and serum albumin concentrations below the normal range have accelerated drug clearance.41,42 The presence of systemic inflammation may therefore increase antibody catabolism in the reticuloendothelial system. This is supported by the suboptimal IFX concentrations that have been observed in patients with severe UC undergoing IFX induction therapy.43 Based on this, we underline that patients with higher grades of inflammation (more severe disease) have a significantly lower likelihood of maintaining sustained response. These patients may benefit from earlier introduction of IFX therapy, which we support, as well as, SONIC study that emphasize the benefit of starting IFX therapy at earlier stages.36 A recent paper by Sandborn et al.,44 with results referring to adalimumab, says that in patients with moderately to severely active CD, weekly dosing of adalimumab may be most effective in the anti-TNF-experienced patients with elevated CRP at baseline, in comparison with adalimumab every other week.

In our data, patients on combination treatment had lower CRP levels at week 14, however, that did not influence final response, need of dose adjustment nor frequency adjustment. Finally, CD patients with longer disease duration responded less well to IFX.

In this analysis, it was possible to evaluate the results of current practice and confirm the important role displayed by CRP as a noninvasive inflammatory marker. According to our results, a higher inflammatory burden at IFX beginning is correlated with a worse response to treatment. The sensitivity and specificity achieved in the presented study isn't high enough to allow the recommendation of the CRP levels proposed by us an indication to stop treatment. However, the high NPV of CRP supports an important role for this marker, once 93% of the patients with baseline CRP levels lower than 15 mg/L and 94% of the patients with CRP levels lower than 4.6 mg/L at week 14 achieved sustained response or response after therapeutic adjustment. Therefore, a decrease in CRP levels at week 14 to levels sufficiently low may be a predictor of good response to treatment. We believe that there is a cut-off CRP from which higher levels are associated with a worse response. It may be due to a more severe disease or to a higher rate of clearance of IFX. Hence, CRP levels together with CRP delta may be a good surrogate marker of IFX response. In clinical practice we propose an evaluation of all patients at week 14 and those with high CRP and low delta should have their IFX efficacy reassessed, however, further prospective studies and external validations are required to evaluate the results achieved.

Conflicts of interest disclosure and funding declaration

None declared.

References

1
Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran's gastrointestinal and liver disease — 2 volume set, 9th ed.
2
Lashner
B.
Inflammatory bowel disease
Carey
W.D.
Cleveland Clinic: Current Clinical Medicine — 2009
 
2009
Saunders
Philadelphia, Pa
3
Feldmann
M.
Elliott
M.J.
Woody
J.N.
Maini
R.N.
Anti-tumor necrosis factor alpha therapy of rheumatoid arthritis
Adv Immunol
 
64
1997
283
350
4
Scallon
B.J.
Moore
M.A.
Trinh
H.
Knight
D.M.
Ghrayeb
J.
Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions
Cytokine
 
7
1995
251
5
Su
C.
Salzberg
B.A.
Lewis
J.D.
Deren
J.J.
Kornbluth
A.
Katzka
D.A.
et al
Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis
Am J Gastroenterol
 
97
2002
2577
6
Lügering
A.
Schmidt
M.
Lügering
N.
Pauels
H.G.
Domschke
W.
Kucharzik
T.
Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway
Gastroenterology
 
121
2001
1145
7
ten Hove
T.
van Montfrans
C.
Peppelenbosch
M.P.
van Deventer
S.J.
Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease
Gut
 
50
2002
206
8
Van den Brande
J.M.
Braat
H.
van den Brink
G.R.
Versteeg
H.H.
Bauer
C.A.
Hoedemaeker
I.
et al
Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease
Gastroenterology
 
124
2003
1774
9
Present
D.H.
Rutgeerts
P.
Targan
S.
Hanauer
S.B.
Mayer
L.
van Hogezand
R.A.
et al
Infliximab for the treatment of fistulas in patients with Crohn's disease
N Engl J Med
 
340
1999
1398
1405
10
Rutgeerts
P.
D'Haens
G.
Targan
S.
Vasiliauskas
E.
Hanauer
S.B.
Present
D.H.
et al
Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease
Gastroenterology
 
117
1999
761
769
11
Hanauer
S.B.
Feagan
B.G.
Lichtenstein
G.R.
Mayer
L.F.
Schreiber
S.
Colombel
J.F.
et al
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial
Lancet
 
359
2002
1541
1549
12
Sands
B.E.
Blank
M.A.
Patel
K.
van Deventer
S.J.
ACCENT II Study. Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study
Clin Gastroenterol Hepatol
 
2
2004
912
920
13
Rutgeerts
P.
Vermeire
S.
Van Assche
G.
Biological therapy for inflammatory bowel diseases
Gastroenterology
 
136
2009
1182
1197
14
Vermeire
S.
Van Assche
G.
Rutgeerts
P.
C-reactive protein as a marker for inflammatory bowel disease
Inflamm Bowel Dis
 
10
2004
661
665
15
Kuhner
I.
C-reactive protein and the acute-phase response
Hosp Pract
 
25
13, 16
1990
21
28
16
Tall
A.R.
C-reactive protein reassessed
N Engl J Med
 
350
2004
1450
1452
17
Vermeire
S.
Van Assche
G.
Rutgeerts
P.
Laboratory markers in IBD: useful, magic, or unnecessary toys?
Gut
 
55
2006
426
431
18
Vermeire
S.
Van Assche
G.
Rutgeerts
P.
The role of C-reactive protein as an inflammatory marker in gastrointestinal diseases
Nat Clin Pract Gastroenterol Hepatol
 
2
2005
580
586
19
Henriksen
M.
Jahnsen
J.
Lygren
I.
Stray
N.
Sauar
J.
Vatn
M.H.
et al
C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study
Gut
 
57
11
Nov. 2008
1518
1523
20
Consigny
Y.
Modigliani
R.
Colombel
J.F.
Dupas
J.L.
Lémann
M.
Mary
J.Y.
A simple biological score for predicting low risk of short-term relapse in Crohn's disease
Inflamm Bowel Dis
 
12
2006
551
557
21
Boirivant
M.
Leoni
M.
Tariciotti
D.
Fais
S.
Squarcia
O.
Pallone
F.
The clinical significance of serum C reactive protein levels in Crohn's disease. Results of a prospective longitudinal study
J Clin Gastroenterol
 
10
1988
401
405
22
Brignola
C.
Campieri
M.
Bazzocchi
G.
Farruggia
P.
Tragnone
A.
Lanfranchi
G.A.
A laboratory index for predicting relapse in asymptomatic patients with Crohn's disease
Gastroenterology
 
91
1986
1490
1494
23
Oussalah
A.
Chevaux
J.B.
Fay
R.
Sandborn
W.J.
Bigard
M.A.
Peyrin-Biroulet
L.
Predictors of infliximab failure after azathioprine withdrawal in Crohn's disease treated with combination therapy
Am J Gastroenterol
 
105
5
May 2010
1142
1149
24
Bitton
A.
Dobkin
P.L.
Edwardes
M.D.
Sewitch
M.J.
Meddings
J.B.
Rawal
S.
et al
Predicting relapse in Crohn's disease: a biopsychosocial model
Gut
 
57
2008
1386
1392
25
Panaccione
R.
Fedorak
R.N.
Aumais
G.
Bernard
E.J.
Bernstein
C.N.
Bitton
A.
et al
Review and clinical perspectives for the use of infliximab in ulcerative colitis
Can J Gastroenterol
 
22
3
Mar. 2008
261
272
26
Stange
E.F.
Travis
S.P.
Vermeire
S.
Reinisch
W.
Geboes
K.
Barakauskiene
A.
et al
European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis
J Crohns Colitis
 
2
1
Mar. 2008
1
23
27
Dignass
A.
Van Assche
G.
Lindsay
J.O.
Lémann
M.
Söderholm
J.
Colombel
J.F.
et al
The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: current management
J Crohns Colitis
 
4
1
Feb. 2010
28
62
28
Vist
G.E.
Hagen
K.B.
Devereaux
P.J.
Bryant
D.
Kristoffersen
D.T.
Oxman
A.D.
Systematic review to determine whether participation in a trial influences outcome
BMJ
 
330
7501
May 21 2005
1175
29
Reinisch
W.
Wang
Y.
Oddens
B.J.
Link
R.
C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn's disease: a post-hoc analysis from ACCENT I
Aliment Pharmacol Ther
 
35
2012
568
576
30
Kiss
L.S.
Szamosi
T.
Molnar
T.
Miheller
P.
Lakatos
L.
Vincze
A.
et al
Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease
Aliment Pharmacol Ther
 
34
8
Oct. 2011
911
922
31
Rubin
D.T.
Mulani
P.
Chao
J.
Pollack
P.F.
Bensimon
A.G.
Yu
A.P.
et al
Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: results from the CHARM trial
Inflamm Bowel Dis
 
18
5
May 2012
818
825
32
Jürgens
M.
Mahachie John
J.M.
Cleynen
I.
Schnitzler
F.
Fidder
H.
van Moerkercke
W.
et al
Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease
Clin Gastroenterol Hepatol
 
9
5
May 2011
421
427
33
Louis
E.
Vermeire
S.
Rutgeerts
P.
De Vos
M.
Van Gossum
A.
Pescatore
P.
et al
A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with − 308 TNF gene polymorphism
Scand J Gastroenterol
 
37
7
Jul. 2002
818
824
34
Colombel
J.F.
Sandborn
W.J.
Rutgeerts
P.
Enns
R.
Hanauer
S.B.
Panaccione
R.
et al
Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial
Gastroenterology
 
132
2007
52
65
35
Schreiber
S.
Rutgeerts
P.
Fedorak
R.N.
Khaliq-Kareemi
M.
Kamm
M.A.
Boivin
M.
et al
A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease
Gastroenterology
 
129
2005
807
818
36
Colombel
J.F.
Sandborn
W.J.
Reinisch
W.
Mantzaris
G.J.
Kornbluth
A.
Rachmilewitz
D.
et al
Infliximab, azathioprine, or combination therapy for Crohn's disease
N Engl J Med
 
362
2010
1383
1395
37
Fagan
E.A.
Dyck
R.F.
Maton
P.N.
Hodgson
H.J.
Chadwick
V.S.
Petrie
A.
et al
Serum levels of C-reactive protein in Crohn's disease and ulcerative colitis
Eur J Clin Invest
 
12
4
1982 Aug
351
359
38
Koelewijn
C.L.
Schwartz
M.P.
Samsom
M.
Oldenburg
B.
C-reactive protein levels during a relapse of Crohn's disease are associated with the clinical course of the disease
World J Gastroenterol
 
14
1
Jan. 7 2008
85
89
39
Mould
D.R.
Green
B.
Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development
BioDrugs
 
24
1
Feb. 1 2010
23
39
40
Ordás
I.
Mould
D.R.
Feagan
B.G.
Sandborn
W.J.
Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms
Clin Pharmacol Ther
 
91
4
Apr. 2012
635
646
41
Fasanmade
A.A.
Adedokun
O.J.
Ford
J.
Hernandez
D.
Johanns
J.
Hu
C.
et al
Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis
Eur J Clin Pharmacol
 
65
12
Dec. 2009
1211
1228
42
Fasanmade
A.A.
Adedokun
O.J.
Blank
M.
Zhou
H.
Davis
H.M.
Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials
Clin Ther
 
33
7
Jul. 2011
946
964
43
Seow
C.H.
Newman
A.
Irwin
S.P.
Steinhart
A.H.
Silverberg
M.S.
Greenberg
G.R.
Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis
Gut
 
59
1
Jan. 2010
49
54
44
Sandborn
W.J.
Colombel
J.F.
D'Haens
G.
Plevy
S.E.
Panés
J.
Robinson
A.M.
et al
Association of baseline C-reactive protein and prior anti-tumor necrosis factor therapy with need for weekly dosing during maintenance therapy with adalimumab in patients with moderate to severe Crohn's disease
Curr Med Res Opin
 
29
5
May 2013
483
493

Figures

Figure 1

Outcome to infliximab treatment in Crohn's disease patients — flowchart. IFX, infliximab; CD, Crohn's disease.

Figure 1

Outcome to infliximab treatment in Crohn's disease patients — flowchart. IFX, infliximab; CD, Crohn's disease.

Figure 2

C-reactive protein levels (mg/L) at baseline median and interquartile range (Mann Whitney test). CRP, C-reactive protein; PNR, primary nonresponse; SR, sustained response; RTA, response after therapeutic adjustment.

Figure 2

C-reactive protein levels (mg/L) at baseline median and interquartile range (Mann Whitney test). CRP, C-reactive protein; PNR, primary nonresponse; SR, sustained response; RTA, response after therapeutic adjustment.

Figure 3

Receiver operating characteristic curves for baseline serum C-reactive protein and primary non response at week 14. CRP, C-reactive protein.

Figure 3

Receiver operating characteristic curves for baseline serum C-reactive protein and primary non response at week 14. CRP, C-reactive protein.

Figure 4

C-reactive protein levels (mg/L) at week 14 — median and interquartile range (Mann Whitney test). CRP, C-reactive protein; PNR, primary nonresponse; SR, sustained response; RTA, response after therapeutic adjustment.

Figure 4

C-reactive protein levels (mg/L) at week 14 — median and interquartile range (Mann Whitney test). CRP, C-reactive protein; PNR, primary nonresponse; SR, sustained response; RTA, response after therapeutic adjustment.

Figure 5

Baseline C-reactive protein and C-reactive protein delta scatter dot — response after therapeutic adjustment and sustained response. CRP, C-reactive protein.

Figure 5

Baseline C-reactive protein and C-reactive protein delta scatter dot — response after therapeutic adjustment and sustained response. CRP, C-reactive protein.

Tables

Table 1

Baseline characteristic of Crohn's disease (CD) patients on infliximab regarding disease duration, time since infliximab first infusion and Montreal classification.

 CD (n = 148) 
Female/male 74/74 
Median age (years: min–max) 36 (14–68) 
Median age at diagnosis (years: min–max) 25 (9–61) 
Median disease duration until 1st IFX (years; min–max) 4 (0–29) 
Median follow-up since diagnosis (years: min–max) 7 (1–24) 
Median follow-up since IFX (months: min–max) 24 (0–134) 
Montreal classification  
Age at diagnosis (%)  
A1 14 (9%) 
A2 119 (81%) 
A3 15 (10%) 
Disease location (%)  
L1 + L1–4 55 (41%) 
L2 + L2–4 25 (18%) 
L3 + L3–4 56 (40%) 
L4 1 (1%) 
Behavior (%)  
B1 + B1p 41 + 21 (44%) 
B2 + B2p 34 + 11 (32%) 
B3 + B3p 18 + 16 (24%) 
Perianal disease (%) 48 (34%) 
 CD (n = 148) 
Female/male 74/74 
Median age (years: min–max) 36 (14–68) 
Median age at diagnosis (years: min–max) 25 (9–61) 
Median disease duration until 1st IFX (years; min–max) 4 (0–29) 
Median follow-up since diagnosis (years: min–max) 7 (1–24) 
Median follow-up since IFX (months: min–max) 24 (0–134) 
Montreal classification  
Age at diagnosis (%)  
A1 14 (9%) 
A2 119 (81%) 
A3 15 (10%) 
Disease location (%)  
L1 + L1–4 55 (41%) 
L2 + L2–4 25 (18%) 
L3 + L3–4 56 (40%) 
L4 1 (1%) 
Behavior (%)  
B1 + B1p 41 + 21 (44%) 
B2 + B2p 34 + 11 (32%) 
B3 + B3p 18 + 16 (24%) 
Perianal disease (%) 48 (34%) 
Table 2

Indications for infliximab, previous treatment and combination treatment in Crohn's disease (CD).

 CD (n = 148) 
Indications for infliximab (%)  
Corticosteroid dependency 29 (20%) 
Corticosteroid resistance 10 (7%) 
Thiopurine intolerance 24 (16%) 
Activity despite thiopurine full-dose 85 (57%) 
Previous treatment (%)  
Immunomodulators 26 (18%) 
Corticosteroids 13 (9%) 
Corticosteroids + immunomodulators (subsequent use) 104 (70%) 
Adalimumab 3 (2%) 
Immunomodulators + adalimumab 2 (1%) 
Combination treatment with azathioprine (%) 118 (80%) 
 CD (n = 148) 
Indications for infliximab (%)  
Corticosteroid dependency 29 (20%) 
Corticosteroid resistance 10 (7%) 
Thiopurine intolerance 24 (16%) 
Activity despite thiopurine full-dose 85 (57%) 
Previous treatment (%)  
Immunomodulators 26 (18%) 
Corticosteroids 13 (9%) 
Corticosteroids + immunomodulators (subsequent use) 104 (70%) 
Adalimumab 3 (2%) 
Immunomodulators + adalimumab 2 (1%) 
Combination treatment with azathioprine (%) 118 (80%) 
Table 3

Patients' characteristics according to disease duration, C-reactive protein (CRP) levels at baseline and week 14, if on combination treatment and response to infliximab.

Characteristics Primary non response (n = 17) Sustained response (n = 79) Response with therapeutic adjustment (n = 28) p-Value 
Gender (%)    0.064 
Male 5 (8.6%) 43 (74.1%) 10 (17.3%)  
Female 12 (18.2%) 36 (54.5%) 18 (27.3%)  
Median age at diagnosis (years: min–max) 25 (14–55) 25 (11–55) 25 (9–61) 0.745 
Median disease duration until 1st infliximab (years: min–max) 6 (0–29) 3 (0–27) 9 (0–29) 0.006 
Median baseline CRP (mg/L: min–max) 26.2 (1–144.3) 9.6 (0.5–200.2) 7.65 (0.9–46.9) 0.02 
Baseline CRP (%)    0.582 
< 3 mg/L 2 (8%) 17 (68%) 6 (24%)  
> 3 mg/L 15 (16%) 57 (62%) 20 (22%)  
Median CRP at week 14 (mg/L: min–max) 9.1 (0.6–110.1) 3.1 (0.1–29) 7.6 (0.4–58.4) 0.007 
CRP at week 14 (%)    0.053 
< 3 mg/L 3 (6%) 39 (78%) 8 (16%)  
> 3 mg/L 10 (14.3%) 40 (57.1%) 20 (28.6%)  
Combination treatment with azathioprine (%) 10 (10.3%) 65 (67%) 22 (22.7%) 0.132 
Characteristics Primary non response (n = 17) Sustained response (n = 79) Response with therapeutic adjustment (n = 28) p-Value 
Gender (%)    0.064 
Male 5 (8.6%) 43 (74.1%) 10 (17.3%)  
Female 12 (18.2%) 36 (54.5%) 18 (27.3%)  
Median age at diagnosis (years: min–max) 25 (14–55) 25 (11–55) 25 (9–61) 0.745 
Median disease duration until 1st infliximab (years: min–max) 6 (0–29) 3 (0–27) 9 (0–29) 0.006 
Median baseline CRP (mg/L: min–max) 26.2 (1–144.3) 9.6 (0.5–200.2) 7.65 (0.9–46.9) 0.02 
Baseline CRP (%)    0.582 
< 3 mg/L 2 (8%) 17 (68%) 6 (24%)  
> 3 mg/L 15 (16%) 57 (62%) 20 (22%)  
Median CRP at week 14 (mg/L: min–max) 9.1 (0.6–110.1) 3.1 (0.1–29) 7.6 (0.4–58.4) 0.007 
CRP at week 14 (%)    0.053 
< 3 mg/L 3 (6%) 39 (78%) 8 (16%)  
> 3 mg/L 10 (14.3%) 40 (57.1%) 20 (28.6%)  
Combination treatment with azathioprine (%) 10 (10.3%) 65 (67%) 22 (22.7%) 0.132 

p-Value: overall comparison between groups.

Author notes

1
The first and second authors contributed equally in the design, conception, analysis, and paper writing.