Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

Primary and Secondary Non-Response to

Infliximab: Mechanisms and Countermeasures

Uni Wong & Raymond K. Cross

To cite this article: Uni Wong & Raymond K. Cross (2017): Primary and Secondary Non-
Response to Infliximab: Mechanisms and Countermeasures, Expert Opinion on Drug Metabolism &
Toxicology, DOI: 10.1080/17425255.2017.1377180

To link to this article: http://dx.doi.org/10.1080/17425255.2017.1377180

Accepted author version posted online: 06

Sep 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iemt20

Download by: [UC Santa Barbara Library] Date: 07 September 2017, At: 07:07
 Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Metabolism & Toxicology

DOI: 10.1080/17425255.2017.1377180
Primary and Secondary Non-Response to Infliximab: Mechanisms and Countermeasures

t
Uni Wong, Raymond K. Cross

ip
Uni Wong, MD

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

Assistant Professor of Medicine

us
685 W. Baltimore Street, Suite 8-00

Baltimore, MD 21201
an
uwong@som.umaryland.edu
M

Raymond K. Cross, MD, MS (Corresponding Author)

ed

Professor of Medicine

Director of the Inflammatory Bowel Disease Program

pt

685 W. Baltimore Street, Suite 8-00

ce

Baltimore, MD 21201

rcross@som.umaryland.edu
Ac

Authors Affiliation: University of Maryland School of Medicine, Department of Medicine,

Division of Gastroenterology and Hepatology, Baltimore, MD

 Abstract

Introduction: Primary and secondary non-response to infliximab are common in patients with

inflammatory bowel disease and remain a management challenge in clinical practice.

Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary

t
ip
and secondary non-response to infliximab in patients with inflammatory bowel disease. Data on

proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

for evaluation and management of non-response to infliximab is provided. Preventative

us
measures are also discussed. Relevant articles were identified after a literature search using

PubMed. Search terms included “infliximab”, “loss of response”, “immunogenicity”, and “drug
an
monitoring”. References of identified articles were also reviewed to identify additional
M
references.

Expert opinion: A common cause for primary and secondary non-response include inadequate
ed

dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-

drug antibody levels. Therapeutic drug monitoring should be done in patients losing response
pt

to infliximab. Use of drug monitoring proactively is still under debate.

ce

Keywords: Infliximab, primary non-response, secondary loss of response, anti-drug antibodies,

immunogenicity, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, therapeutic

Ac

drug monitoring.

2
 I. Introduction

Infliximab (IFX), a monoclonal IgG1 antibody against tumor necrosis factor-alpha (TNF-α), is

effective for induction and maintenance of remission in inflammatory bowel disease (IBD) –

t
namely Crohn’s disease (CD) and ulcerative colitis (UC) [1, 2]. It has revolutionized the

ip
treatment of IBD, ameliorating symptoms, allowing for sparing of long-term steroid use, and

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

decreasing the rate of hospitalizations and surgeries [1, 2]. However, more than one third of

us
patients do not respond to IFX [3]. Amongst those who demonstrate a response initially, 30-

50% lose response over the course of one year [1, 4]. Primary non-responders are those who
an
have no clinical response during initial treatment with IFX. Secondary non-responders are those

who lose response to IFX therapy over time. Distinguishing between these two types of
M

treatment failure is important because they have different mechanisms and the management
ed

strategies differ. This article describes the epidemiology, mechanisms, risk factors and

management strategies for both primary and secondary non-response to IFX.

pt
ce

II. Primary Non-Response to Infliximab

Primary non-response (PNR) is defined as lack of improvement in clinical signs or symptoms

Ac

after initiating induction therapy with IFX. Clinical response is assessed in clinical trials and in

some practices using the Crohn’s Disease Activity Index (CDAI) or the Harvey Bradshaw Index

(HBI) for CD; the Mayo Score, the Truelove and Witts’ severity index or the Simple Clinical

Colitis Activity Index (SCCAI) is used for UC [1, 2, 5-7]. In the case of perianal CD, a complete

3
 response is defined as absence of any draining fistula on physical exam [8]. In the A Crohn’s

Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen in Patients

with Fistulizing Crohn’s Disease (ACCENT) II trial, a response was defined as a reduction of at

least 50% from baseline in the number of draining fistulae at consecutive visits four or more

t
weeks apart [4]. The standard induction dose for IFX is 5mg/kg given at week 0, week 2 and

ip
week 6, with the first maintenance dose given at week 14. There is no standardized definition

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

on when a patient is deemed a PNR; however, lack of clinical improvement by week 14 is

us
generally considered PNR [1, 4, 9]. Pragmatically, determination of PNR depends on the severity

of symptoms. For example, in a patient with severe disease, an earlier determination of

an
response is needed, perhaps shortly after the 2nd infusion. For patients with less severe disease

or a partial response to therapy, assessment after completion of induction therapy is indicated.

M

a. Epidemiology. Despite its efficacy in induction and maintenance of remission in both CD and
ed

UC [1, 2, 4], PNR to anti-TNF therapy occurs in up to 40% of patients in clinical trials and up to

20% in clinical series [1, 5, 10, 11]. In a retrospective analysis of prospectively collected data,
pt

Sprakes et al. noted that 16 (9.8%) of 163 CD patients who underwent three-dose induction

therapy with IFX had no response [5]. Similarly, in another retrospective study of 560 patients
ce

with IBD (353 patients with CD and 207 patients with UC) who received IFX as a first anti-TNF
Ac

therapy, 33 (9%) patients with CD and 48 (23%) with UC had PNR after median of 3 infusions

[12].Due to the lack of standardization of IFX dosing and limited data, the true incidence of PNR

to IFX in severe UC patients who are hospitalized remains unclear [13, 14]. In a randomized

double-blind, placebo-controlled trial by Jarnerot et al., 7 (29%) of 24 steroid-refractory severe

UC patients who received a single dose of IFX 5mg/kg infusion required colectomy within 3

4
 months [13]. In a retrospective study consisting of 41 hospitalized patients with acute severe

steroid-refractory UC who were treated with standard induction IFX therapy, 5 (12%) of 41

patients underwent colectomy within 3 months [14].

b. Mechanisms and risk factors. The exact mechanism by which PNR to IFX occurs has not been

t
elucidated [15]. Since IFX is administered intravenously, there is immediate central distribution

ip
resulting in less variability in drug exposure between individuals [15]. However, males and

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

those with higher body mass index have increased drug clearance [15]. Other factors that seem

us
to increase the risk of PNR include small bowel involvement, smoking, disease duration greater

than 2 years, high IL-8 level, high TNF:CRP ratio, and genetic mutations such as FAS-L and
an
caspase-9 in the apoptosis-related genes [9, 10]. These various factors collectively may account

for the variability in clinical response amongst individuals who receive IFX [15] (Table 1). In
M

addition, the degree of inflammatory burden appears to impact clinical response to IFX. In a
ed

study consisting of 59 patients with UC who received IFX 5mg/kg at weeks 0, 2 and 6, Olsen et

al. found that patients with higher pre-treatment colonic TNF-α concentration had a decreased
pt

likelihood of achieving clinical or endoscopic remission [16]. It has also been demonstrated that

intestinal clearance of immunoglobulin is related to disease severity, with leakage of drug in

ce

stools when there is high inflammatory burden [17]. Lack of response to IFX occurs when there
Ac

is insufficient drug to block the excess TNF-α in serum and tissue. Therefore, patients with

severe disease and systemic inflammatory burden may require higher doses of IFX to achieve

clinical efficacy.

Patients with severe colitis can serve as a case study for various mechanisms that contribute to

accelerated drug clearance and PNR. Patients with severe colitis often have high serum c

5
 reactive protein (CRP) levels and low serum albumin. In UC patients, low albumin has been

associated with high rate of IFX clearance [18]. In the rheumatology literature, high pre-

treatment serum CRP correlates with low IFX trough levels at week 14 (r(s)=-0.43, p<0.001)[19].

In a retrospective study consisting of 99 anti-TNF-naïve UC patients who had PNR to IFX,

t
Papamichael et al. found that baseline albumin < 40 g/l and CRP > 5mg/l were independent

ip
predictors for colectomy [20]. In addition, severe mucosal ulcerations may be present which

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

can serve as a “sieve” for IFX. Brandse and colleagues evaluated fecal loss of IFX in 30 patients

us
with severe colitis. They found that non-responders to IFX had higher fecal and lower serum IFX

concentrations [21]. Providers have increasingly recognized these factors and have adjusted IFX
an
dosing at the initiation of treatment. In a retrospective analysis of 50 patients including 15 who

were treated with an accelerated IFX treatment protocol of 3 doses of 5 mg/kg within a median
M
of 24 days, it was shown that accelerated IFX treatment reduced colectomy rates from 40% in

those receiving standard dosing to 7% (p=0.039) [22].

ed

c. Management. Patients with PNR to IFX have been shown to have a poor prognosis [12, 20].
pt

In a retrospective study by Buhl et al., it was shown that compared to responders, non-

responders to IFX were found to be at increased risk for surgery with odds ratio of 6.3 (95% CI
ce

3.8-10.6, P<0.0001) [12]. In a retrospective study by Papamichael et al., 55 (55.6%) of 99 anti-

Ac

TNF-naïve UC patients who had PNR to IFX underwent colectomy by the end of the follow-up

period at a median of 3.2 years [20]. Thus, early recognition and management is important.

The management of PNR to IFX begins with an assessment to confirm that the symptoms are

related to active IBD. Other mechanisms for symptoms are common in patients with IBD,

particularly in those with CD. Concurrent irritable bowel syndrome, anxiety, depression, small

6
 intestinal bacterial overgrowth, altered anatomy after intestinal resection, short bowel

syndrome, choleretic diarrhea, and adhesions can all result in gastrointestinal symptoms similar

to those of active IBD. Exclusion of concurrent infection, particularly Clostridium difficile and

Cytomegalovirus, is critical. Another potential reason for non-response to IFX is the presence of

t
complicated CD. Most strictures have a component of fibrosis; in fact most inflammatory

ip
strictures are also fibrotic [23]. Thus, despite improvement or reversal of the inflammatory

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

component of strictures, fibrosis is likely to persist with possible chronic symptoms. A study by

us
Nepal and colleagues demonstrated that patients with strictures associated with any of the

following factors were unlikely to respond to anti-TNF therapy: proximal small bowel dilation,
an
mesenteric stranding, internal fistula, abscess, and small bowel obstruction [24]. In patients

with perianal CD, exclusion of an underlying abscess that was not adequately drained at the
M
time of initiation of IFX is an important consideration.
ed

Once active IBD is confirmed based on objective data including endoscopy, imaging, and

biomarkers, a number of factors should be considered. First, is the dose of IFX sufficient?
pt

Second, has early immunogenicity occurred with the development of antibodies to IFX? Third,

does the disease process require more than one mechanism of action to control the disease?
ce

Lastly, is the disease process is not mediated by TNFα?

Ac

In one prospective randomized, double-blinded, controlled clinical trial (TAILORIX) consisting of

122 patients with Crohn’s disease, D’Haens and colleagues found that proactive therapeutic

drug monitoring (TDM) was not superior than dose escalation based on clinical symptoms alone

[25]. In clinical practice, however, therapeutic drug monitoring seems to be more cost-effective

than empiric dose escalation in patients who lose responsiveness to infliximab [26]. Although

7
 not validated with prospective studies, TDM can be helpful in management of PNR. If no anti-

drug antibodies (ADA) are present and the drug level is sub-therapeutic, one strategy to achieve

response is dose escalation and/or shortening the interval of dosing.

It is not clear if achieving high drug levels will result in a response or rather that high drug levels

t
are a marker of response to treatment. Our group has shown that assessment of an anti-TNF

ip
levels proactively after initiating therapy is associated with higher rates of clinical and

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

endoscopic response, and persistence to treatment at 1 year [27]. The optimal IFX level,

us
however, is not known. The utility of performing TDM during the induction phase of IFX is not

clear. A recent analysis demonstrated that IFX levels of ≥15μg/ml at week 6 are associated with
an
mucosal healing [28]. In the post-hoc analyses of the data from the Active Ulcerative Colitis

Trials (ACT) 1 and 2, Adedokun and colleagues noted that a week 6 IFX threshold of 22μg/ml
M

was associated with clinical response at week 8 [29]. It is important to keep in mind that there
ed

is no absolute cut off value for therapeutic trough level, but rather a range of values that may

vary depending on the assay used to measure the drug and the anti-drug antibody level,
pt

severity of the disease and the treatment target (i.e. induction versus maintenance of

remission, clinical response versus endoscopic response) [30].

ce

IFX levels needed to achieve complete response in patients with perianal disease is even less
Ac

clear, although a recent study reported that levels ≥10.1μg/ml are needed [31]. In patients

with perianal involvement, controlling sepsis with antibiotics and an exam under anesthesia is

very important. Both retrospective and prospective studies have demonstrated that response

to IFX is increased when these measures are implemented before initiation of IFX [32, 33].

8
 If ADA are present and the drug concentrations are low, we recommend either changing to

another anti-TNF while adding a concurrent immunomodulatory or changing to a biologic with

a different mechanism of action. What ADA levels are clinically significant remains to be further

investigated. However, in a recent analysis by Yanai et al., using the threshold of IFX ADA

t
>9μg/ml equivalent identified patients who did not respond to dose escalation with 90%

ip
specificity [34]. Adding a concurrent immunomodulator while changing to another anti-TNF

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

may both suppress antibody formation and independently raise drug levels. If IFX levels are

us
adequate, most providers recommend changing to another class of medications (anti-integrin,

anti-IL 12/23, immune suppressant, or investigational agent). If patients experience a partial

an
response to IFX, adding an immunomodulator such as thiopurine or methotrexate can be

considered.
M

d. Special considerations. In addition to the risk factors described above that are associated
ed

with PNR, it is important to emphasize that patients with severe colitis may require a higher

induction dose and/or an accelerated dosing schedule due to increased IFX clearance in setting
pt

of high inflammatory burden and intestinal drug leakage [16, 17, 35]. In a systematic review,

Hindryckx and colleagues found that infliximab dose intensification could reduce early (3-
ce

month) colectomy rate by up to 80% in case-controlled studies [36]. Another patient population
Ac

that may require special consideration are patients with perianal CD. Although an IFX trough

level of 3-10 µg/mL appears to be the therapeutic range for luminal disease in IBD patients [37,

38], patients with perianal CD may require IFX trough levels as high as ≥ 10.1 µg/mL to achieve

fistula healing [31]. Thus, early drug monitoring and treating to a therapeutic target should be

9
 considered in these patient populations; prospective studies validating this approach are

needed.

III. Secondary Non-Response to Infliximab

t
ip
Secondary non-response, also known as loss of response (LOR), describes those cases where

the patient had an initial clinical improvement during or after induction of IFX but later

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

developed a relapse of disease. Although there are no well-defined criteria for LOR [39],

us
recurrence of symptoms after successful induction therapy is a reasonable criterion. The time

frame at which LOR occurs can range from weeks to years after induction of therapy [1, 4].
an
a. Epidemiology. The rate at which LOR occurs in IBD patients is difficult to determine due to
M
lack of standardized definitions for LOR. On average, 37% of patients who complete standard

induction of IFX will lose response [40]. In the ACCENT I trial, approximately 40% of patients
ed

with CD treated with IFX lost response despite maintenance therapy with IFX 5mg/kg every 8

weeks or 10mg/kg every 8 weeks [1]. In the pivotal trial examining the efficacy of IFX for
pt

treatment of perianal CD, 64% of patients developed recurrence of draining fistula at week 54
ce

after receipt of 3 doses of IFX [8]. The high rate of LOR in this cohort is likely due to lack of

maintenance therapy. In the ACCENT II trial, the LOR rate, defined as at least one newly
Ac

developed fistula-related abscess, was much lower at 48 (17%) out of 282 patients [4]. In the

Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC), 75 (44%) of

169 patients who received IFX were in steroid-free clinical remission at week 26, but only 59

(35%) patients were in clinical remission at week 50 [41]. As for the patients who received

10
 combination therapy with IFX and azathioprine, 96 (57%) of 169 patients were in steroid-free

clinical remission at week 26, and the number of patients in remission at week 50 decreased to

78 (46%) [41].

LOR in the UC patient population is also common. In the ACT 1 and ACT 2 trials, clinical

t
response after IFX therapy was seen in 62-69% of UC patients at week 8, but only 51-60% at

ip
week 30, and even lower at 44-45% by week 54 [2]. In the UC SUCCESS trial, 78 patients were

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

randomized to receive combination therapy with IFX and azathioprine, and clinical response

us
was noted in 85.9% of patients at week 8 which was later decreased to 76.9% at week 16. A

similar pattern was seen in the group who received IFX monotherapy with 88.3% of patients in
an
clinical remission at week 8 and only 68.8% at week 16 [42]. These studies highlight the

difficulty in maintaining clinical response in both CD and UC patients.

M

b. Mechanisms and risk factors. LOR to an anti-TNF is thought to occur when there is not
ed

enough active drug available, either through degradation and elimination, or through

inactivation with the formation of ADA [15]. Degradation and elimination of monoclonal
pt

antibodies occurs mainly in the reticuloendothelial system (RES) [43]. The Brambell receptor
ce

(FcRn) expressed in the cells within the RES is responsible for maintaining a homeostasis

between immunoglobulin (IgG) and albumin [15, 44]. The half-life of the IgG is inversely
Ac

proportional to the concentration, however. This system is saturated at high concentrations

with an inverse relationship between concentration and half-life of the protein [45]. As a result,

when there are high levels of endogenous IgG such as in the case of chronic inflammatory

states, the half-life of exogenously administered monoclonal antibodies may shorten [15]. This,

in turn, results in LOR in patients with high inflammatory burden such as patients with severe

11
 colitis. As discussed above in the section on PNR, other factors not associated with the

inflammatory burden are associated with accelerated drug clearance, including male gender,

high body mass index, and lack of concurrent immune suppression.

Immunogenicity also plays a critical role in LOR. Development of ADA leads to immune complex

t
formation which can induce drug clearance by the RES system, thus diminishing the

ip
effectiveness of these drugs [46]. One way ADA can occur is with episodic rather than

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

scheduled administration of the anti-TNF. When examining ADA levels among 23 CD patients

us
who received episodic infusion after IFX induction compared to 82 CD patients who received

scheduled therapy at 6- to 8-week intervals, Maser et al. found that episodic treatment was
an
associated with a higher rate of ADA formation (39% vs. 16%, P = 0.036) [47]. ADA developed in

38% of patients not receiving maintenance IFX in ACCENT I [1].

M

Another method by which ADA can develop is when the anti-TNF is administered as a
ed

monotherapy rather than as a combination therapy with an immunomodulator. In a

retrospective study consisting of 155 IBD patients who had IFX and ADA levels measured
pt

approximately 1 year after initiation of therapy, concomitant use of immunomodulator was

ce

associated with lower rate of ADA (14% vs. 29%, P<0.03) [48]. Similarly, in the ACCENT I trial,

patients who were on a concomitant immunomodulator were less likely to have antibodies to
Ac

IFX (4%), compared to those who were on concomitant steroid alone (17%) and those who

were on neither a concomitant steroid nor immunomodulator (18%) [1]. Presence of ADA not

only affect the efficacy of the drug, but it is also associated with infusion reactions [1].

12
 c. Management. When LOR to an anti-TNF is suspected, an assessment for active inflammation

and/or complications of IBD should be initiated as described above (Figure 1). Measurement of

the drug concentration and ADA levels can guide changes in treatment [49, 50]. The American

Gastroenterological Association conditionally recommends measuring therapeutic drug level in

t
patients with active IBD to guide treatment changes [51].

ip
ADA present. As described previously, the presence of ADA is associated with LOR and possible

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

infusion reactions. In the presence of high ADA (>9 µg/ml), therapy should be changed to

us
another anti-TNF or a biologic of a different class such as vedolizumab or ustekinumab, with or

without an immunomodulator to prevent future immunogenicity [52]. In our opinion, addition

an
of an immunomodulator if tolerated is required in patients changing to another biologic

because of development of immunogenicity with the first biologic agent. In the retrospective
M

study conducted by Afif et al., 35 (23%) out of 155 patients were noted to have detectable ADA;
ed

changing their therapy to a different anti-TNF resulted in a complete or partial response in 92%,

whereas dose escalation resulted in a response rate in only 17% [48]. It is unclear which of
pt

these patients had high levels of ADA and which ones had low levels of ADA. Alternatively, if the

ADA level is low, one can consider first adding an immunomodulator rather than switching
ce

therapy to another biologic. In small case series from Israel, adding an immunomodulator was
Ac

shown to be effective in lowering ADA while increasing anti-TNF trough levels, resulting in

restoration of clinical response [53, 54].

ADA not present. If ADA are not present and the IFX trough level is low, escalation of the dose

and/or shortening the frequency of dosing can achieve clinical response in up to 86% of

patients, while changing therapy to another anti-TNF achieves clinical response in only 33% of

13
 patients [48, 55]. If ADA are not present and IFX trough levels are adequate, it is important to

document that active inflammation is present. In the study by Afif and colleagues, over 60% of

patients had no inflammation present and most patients were maintained on IFX at the current

dose. If active inflammation is confirmed, the patient is unlikely to respond to dose

t
intensification [48]. In the retrospective analysis published by Yanai and colleagues, IFX trough

ip
level >3.8 μg/ml identified patients who failed to respond to dose escalation or a switch to

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

another anti-TNF with 90% specificity [34]. In these cases, changing therapy to another class of

us
biologic is recommended. As discussed previously, stricturing CD is a common cause of non-

response and LOR. LOR when a stricture is present may not represent a failure of anti-TNF but
an
may in fact be progression of the underlying fibrotic process which is not TNF-mediated. The

optimal IFX level is also a “moving target”. Achieving an IFX level at trough between 3 and 10
M
μg/ml is usually adequate [37, 38].
ed

d. Prevention. Strategies to prevent LOR include selection of an appropriate patient for

treatment (active inflammation confirmed, no or low risk stricture present), scheduled

pt

maintenance therapy and use of concomitant immunomodulator. Scheduled administration of

an anti-TNF is favored over episodic treatment because of lower risk of ADA formation and
ce

lower risk of LOR [1, 47, 56]. Use of concomitant immunomodulator can prevent LOR by
Ac

reducing immunogenicity. In patients receiving episodic IFX therapy, Baert et al. found that the

rate of ADA formation was significantly lower in those receiving concomitant

immunosuppressive therapy at 43%, vs. 75% (P<0.01) [57]. Vermeire et al. reported similar

findings; patients receiving concomitant immunomodulator had lower incidence of ADA (46%

vs. 73%, P<0.001). No differences were noted in the formation of ADA between azathioprine

14
 (48%) and methotrexate (44%) [58]. In patients receiving scheduled IFX therapy, use of

concomitant immunomodulator has also been shown to reduce risk of immunogenicity (10% vs.

18%, P=0.02) [56].

Furthermore, use of a concurrent immunomodulator has been shown to improve clinical

t
response rates [41, 42]. In the SONIC trial, combination therapy with IFX and azathioprine was

ip
shown to be more effective in achieving as well as maintaining steroid-free remission than IFX

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

alone at week 50, 78 (46.2%) of 169 patients vs. 59 (34.9%) of 169 patients (P=0.04) [41].

us
Similarly, in the UC SUCCESS trial, there were more patients in the combination therapy group

in clinical remission than in the IFX monotherapy group when patients were followed out to
an
week 16, 39.7% vs. 22.1% (P= 0.017) [42].
M
Because LOR occurs in the setting of ADA formation and sub-therapeutic drug concentrations,

some have recommended proactive therapeutic drug monitoring to optimize therapy and
ed

prevent LOR [15]. IBD patients with higher drug trough concentrations clearly have better

outcomes [47, 59]. A study by Baert et al. demonstrated that those with luminal or fistulizing
pt

Crohn’s disease who had a week 4 IFX concentration of ≥12 µg/ml have a significantly longer
ce

median duration of response than those with level ≤ 12 µg/ml (81.5 days vs. 68.5 days, P<0.01)

[57].
Ac

Cheifetz and colleagues were the first to report that proactive monitoring of IFX improved

persistence with therapy. When IFX levels were maintained between a ranges of 5-10 μg/ml,

less than 10% of patients experienced LOR [60]. Our group has also demonstrated that

persistence is higher in patients undergoing proactive monitoring of both IFX and adalimumab,

15
 with over 90% of patients on anti-TNF one year after starting therapy [27]. These studies had

limitations as they were in retrospective nature [27, 60, 61]. In the Trough Concentration

Adapted Infliximab Treatment (TAXIT) randomized controlled trial, all patients on IFX

maintenance therapy underwent a one-time measure of IFX levels. If the IFX level was <

t
3μg/ml, patients underwent dose optimization. Interestingly, remission rates increased from

ip
68% to 90% with a single dose adjustment. Patients were then randomized to further

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

adjustment based on symptoms or drug levels. Rates of steroid-free remission were equivalent

us
after one year; however relapse rates were only 6% in the therapeutic drug monitoring group

compared to the control arm [62]. Despite these provocative studies, newly published
an
guidelines do not support proactive assessment of anti-TNF levels [49, 51].

IV. Conclusion. Despite the clinical advances made with anti-TNF therapy, about one-third of
M

patients are primary non-responders [3]. Amongst those who demonstrate an initial response,
ed

up to half of the patients eventually lose response [1, 4]. Managing primary and secondary non-

response is a frequent challenge in clinical practice. The first step in management of these cases
pt

is to determine whether the symptoms are truly related to active IBD, because symptoms of

active IBD overlap with other disorders including infection, fibro-stenotic stricture, irritable
ce

bowel syndrome, small intestinal bacterial overgrowth, bile salt diarrhea, dietary intolerance,
Ac

short bowel syndrome, and symptoms related to altered surgical anatomy [39].

The reasons for PNR vary. Clearly, a subset of patients cannot respond to anti-TNF therapy.

Second, anti-TNF therapy may be started at a point in time when a complication of CD has

already developed or when inflammation is “deep seated” and unlikely to respond to

treatment. Although speculative, a proportion of patients with PNR may be under-dosed with

16
 IFX, particularly in patients with severe colitis and perianal CD. Therapeutic drug monitoring can

be used in the setting of PNR to guide adjustments in IFX therapy to induce a clinical response.

However, additional research is needed to determine the optimal IFX levels during the

induction phase of treatment.

t
Secondary non-response often occurs due to inadequate anti-TNF levels with resultant

ip
immunogenicity and formation of ADA. Administering IFX in a scheduled rather than episodic

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

fashion, and using a concomitant immunomodulator can help optimize drug levels and prevent

us
immunogenicity. Current guidelines do not recommend proactive drug monitoring to prevent

LOR. When LOR occurs, therapeutic drug levels should be obtained to guide changes in
an
management. Patients with low IFX levels and low or absent ADA can undergo dose escalation.

Patients with low IFX levels and high ADA levels should change biologic and start concurrent
M

immune suppression. The presence of therapeutic drug levels should prompt restaging of
ed

disease as the majority of these patients have no evidence of active inflammation.

pt

V. Expert opinions
ce

- Our interpretation of the available data. Primary and secondary non-response is a

common problem in clinical trials and clinical practice. Certain populations including
Ac

patients with severe colitis or perianal CD require special considerations when deciding

on the dose and frequency of IFX administration and optimal IFX level. Scheduled rather

than episodic treatment is favored in order to avoid immunogenicity and LOR.

Concomitant use of immunomodulator can help prevent immunogenicity as well,

17
 resulting in higher rate of clinical response and longer duration of clinical remission.

Therapeutic drug monitoring is a useful tool to assess and manage both primary and

secondary non-response, although interpretation of results and subsequent

management is more clear in secondary non-response.

t
- Key findings and weaknesses in the research. It is clear that patients, such as those with

ip
severe colitis, have lower response rates to anti-TNF therapy. One retrospective study

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

demonstrated that optimizing dose at the time of induction therapy was more effective

us
than conventional dosing. However, prospective studies are needed to personalize

dosing to improve initial response. Additionally, further prospective studies are needed
an
to assess whether proactive monitoring can prevent LOR over time and if proactive

monitoring can be used instead of concurrent immune suppression as a strategy to

M
reduce immunogenicity. Also, prospective studies are needed examining not only the

clinical outcomes of TDM versus empiric dose escalation, but the difference in
ed

healthcare cost using these strategies. Lastly, more studies are needed to define the

optimal drug level of IFX (and other biologics) needed to induce a clinical response and
pt

mucosal healing.
ce

- Ultimate goal in this field. The ultimate goal in this field would be to better understand

the pharmacokinetics (how the body affects the drug) and the pharmacodynamics (how
Ac

the drug affects the body) of biologic therapy, and to understand why certain individuals

do not respond despite adequate or even high drug trough concentrations.

Furthermore, we need to be able to identify patients who are at risk for primary or

secondary non-response and tailor their therapy accordingly.

18
 - Where do you see this field going in the coming years? With more data on the

pharmacokinetics and the pharmacodynamics of biologic therapy, we can offer

personalized medicine, individualizing treatment dose and/or need for concomitant

immunomodulator.

t
ip
Article Highlights:

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

• Primary and secondary loss of response to infliximab is a common clinical challenge.

us
• High inflammatory burden can impact clinical response to infliximab due to intestinal
an
clearance of immunoglobulin and accelerated clearance of drug.

• Complications of Crohn’s disease including stricture and abscess may be associated with
M
primary non-response.

• Although not validated in prospective studies, therapeutic drug monitoring should be

ed

considered in patients who lose response to infliximab.

• Patients with loss of response while having therapeutic trough concentration would
pt

benefit from a biologic of different class

ce

Figure 1. Management of Loss of Response to Infliximab

Ac

Funding

This paper is not funded

Declaration of Interest

19
 R Cross has participated in advisory boards and consulting for Janssen. The authors have no

other relevant affiliations or financial involvement with any organization or entity with a

financial interest in or financial conflict with the subject matter or materials discussed in the

manuscript apart from those disclosed.

t
ip
References

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

Papers of special note have been highlighted as:

us
* of interest
an
** of considerable interest
M
1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the
ACCENT I randomised trial. Lancet, 2002. 359(9317): p. 1541-9.
2. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy
for ulcerative colitis. N Engl J Med, 2005. 353(23): p. 2462-76.
ed

3. Peyrin-Biroulet L, Deltenre P, de Suray N, et al. Efficacy and safety of tumor necrosis factor
antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol
Hepatol, 2008. 6(6): p. 644-53.
4. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing
pt

Crohn's disease. N Engl J Med, 2004. 350(9): p. 876-85.

5. Sprakes MB, Ford AC, Warren L, et al. Efficacy, tolerability, and predictors of response to
infliximab therapy for Crohn's disease: a large single centre experience. J Crohns Colitis, 2012.
ce

6(2): p. 143-53.
6. Sands BE, Tremaine WJ, Sandborn WJ, et al. Infliximab in the treatment of severe, steroid-
refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis, 2001. 7(2): p. 83-8.
7. Gavalas E, Kountouras J, Stergiopoulos C, et al. Efficacy and safety of infliximab in steroid-
Ac

dependent ulcerative colitis patients. Hepatogastroenterology, 2007. 54(76): p. 1074-9.

8. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with
Crohn's disease. N Engl J Med, 1999. 340(18): p. 1398-405.
9. Billiet T, Cleynen I, Ballet V, et al. Prognostic factors for long-term infliximab treatment in Crohn's
disease patients: a 20-year single centre experience. Aliment Pharmacol Ther, 2016. 44(7): p.
673-83.
10. Ben-Horin S, Kopylov U, and Chowers Y. Optimizing anti-TNF treatments in inflammatory bowel
disease. Autoimmun Rev, 2014. 13(1): p. 24-30.

20
 11. Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel
disease: systematic review and meta-analysis. Am J Gastroenterol, 2011. 106(4): p. 644-59, quiz
660.
12. Buhl S, Steenholdt C, Rasmussen M, et al. Outcomes After Primary Infliximab Treatment Failure
in Inflammatory Bowel Disease. Inflamm Bowel Dis, 2017.
13. Jarnerot 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(7): p. 1805-11.
14. Seah D, Choy MC, Gorelik A, et al. Examining maintenance care following infliximab salvage

t
therapy for acute severe ulcerative colitis. J Gastroenterol Hepatol, 2017.

ip
15. Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel
disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther, 2012. 91(4): p. 635-46.
16. Olsen T, Goll R, Cui G, et al. TNF-alpha gene expression in colorectal mucosa as a predictor of

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

remission after induction therapy with infliximab in ulcerative colitis. Cytokine, 2009. 46(2): p.
222-7.
17. Kapel N, Meillet D, Favennec L, et al. Evaluation of intestinal clearance and faecal excretion of

us
alpha 1-antiproteinase and immunoglobulins during Crohn's disease and ulcerative colitis. Eur J
Clin Chem Clin Biochem, 1992. 30(4): p. 197-202.
18. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in
an
patients with ulcerative colitis. Eur J Clin Pharmacol, 2009. 65(12): p. 1211-28.
19. Wolbink GJ, Voskuyl AE, Lems WF, et al. Relationship between serum trough infliximab levels,
pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients
with rheumatoid arthritis. Ann Rheum Dis, 2005. 64(5): p. 704-7.
M
20. Papamichael K, Rivals-Lerebours O, Billiet T, et al. Long-Term Outcome of Patients with
Ulcerative Colitis and Primary Non-response to Infliximab. J Crohns Colitis, 2016. 10(9): p. 1015-
23.
21. Brandse JF, van den Brink GR, Wildenberg ME, et al. Loss of Infliximab Into Feces Is Associated
ed

With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology,
2015. 149(2): p. 350-5 e2.
22. Gibson DJ, Heetun ZS, Redmond CE, et al. An accelerated infliximab induction regimen reduces
the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol
pt

Hepatol, 2015. 13(2): p. 330-335 e1.

23. Adler J, Punglia DR, Dillman JR, et al. Computed tomography enterography findings correlate
with tissue inflammation, not fibrosis in resected small bowel Crohn's disease. Inflamm Bowel
ce

Dis, 2012. 18(5): p. 849-56.

24. Nepal S, Bahuva R, Shen B, et al. Development and Validation of a Novel Enterography-Based
Stricture Severity Score (SSS) to Predict the Need for Surgery in Patients With Stricturing Crohn's
Disease. Gastroenterology, 2012. 142(5): p. S190-S191.
Ac

25. D'Haens G, Vermeire S, Lambrecht G, et al. Drug-concentration versus symptom-driven dose

adaptation of Infliximab in patients with active Crohn's disease: a prospective, randomised,
multicentre trial (Tailorix). Journal of Crohns & Colitis, 2016. 10: p. S24-S24.
26. Velayos FS, Kahn JG, Sanborn WJ, et al. A test-based strategy is more cost effective than empiric
dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. Clin
Gastroenterol Hepatol, 2013. 11(6): p. 654-66.
27. Perinbasekar RA, Brown A, Syed N, et al. Proactive Monitoring of Infliximab (IFX) and
Adalimumab (ADA) Drug and Anti-Drug Antibody Concentration Utilizing the Labcorp Assay in
Inflammatory Bowel Disease (IBD) Patients. Gastroenterology. 152(5): p. S392.Abstract
presented at Digestive Disease Week, May 2017.

21
 28. Papamichael K, Van Stappen T, Vande Casteele N, et al. Infliximab Concentration Thresholds
During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With
Ulcerative Colitis. Clin Gastroenterol Hepatol, 2016. 14(4): p. 543-9.
29. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of
infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology, 2014. 147(6): p.
1296-1307 e5.
30. Casteele NV, Herfarth H, Katz J, et al. American Gastroenterological Association Technical Review
on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel
Diseases. Gastroenterology, 2017.

t
31. Yarur AJ, Kanagala V, Stein DJ, et al. Higher infliximab trough levels are associated with perianal

ip
fistula healing in patients with Crohn's disease. Aliment Pharmacol Ther, 2017. 45(7): p. 933-940.
32. Regueiro M and Mardini H. Treatment of perianal fistulizing Crohn's disease with infliximab
alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis,

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

2003. 9(2): p. 98-103.

33. Schwartz DA, White CM, Wise PE, et al. Use of endoscopic ultrasound to guide combination
medical and surgical therapy for patients with Crohn's perianal fistulas. Inflamm Bowel Dis,

us
2005. 11(8): p. 727-32.
34. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with
outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol
Hepatol, 2015. 13(3): p. 522-530 e2.
an
35. Ungar B, Mazor Y, Weisshof R, et al. Induction infliximab levels among patients with acute severe
ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment
Pharmacol Ther, 2016. 43(12): p. 1293-9.
M
36. Hindryckx P, Novak G, Vande Casteele N, et al. Review article: dose optimisation of infliximab for
acute severe ulcerative colitis. Aliment Pharmacol Ther, 2017. 45(5): p. 617-630.
37. Ungar B, Levy I, Yavne Y, et al. Optimizing Anti-TNF-alpha Therapy: Serum Levels of Infliximab
and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel
ed

Diseases. Clin Gastroenterol Hepatol, 2016. 14(4): p. 550-557 e2.

38. Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide
dosing for patients with inflammatory bowel disease. Gastroenterology, 2015. 148(7): p. 1320-9
e3.
pt

39. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF
therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological
aspects. J Crohns Colitis, 2010. 4(4): p. 355-66.
ce

40. Gisbert JP and Panes J. Loss of response and requirement of infliximab dose intensification in
Crohn's disease: a review. Am J Gastroenterol, 2009. 104(3): p. 760-7.
41. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy
for Crohn's disease. N Engl J Med, 2010. 362(15): p. 1383-95.
Ac

42. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine
is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology, 2014.
146(2): p. 392-400 e3.
43. Wang W, Wang EQ, and Balthasar JP. Monoclonal antibody pharmacokinetics and
pharmacodynamics. Clin Pharmacol Ther, 2008. 84(5): p. 548-58.
44. Brambell FW, Hemmings WA, and Morris IG. A Theoretical Model of Gamma-Globulin
Catabolism. Nature, 1964. 203: p. 1352-4.
45. Morell A, Terry WD, and Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin
Invest, 1970. 49(4): p. 673-80.

22
 46. Rojas JR, Taylor RP, Cunningham MR, et al. Formation, distribution, and elimination of infliximab
and anti-infliximab immune complexes in cynomolgus monkeys. J Pharmacol Exp Ther, 2005.
313(2): p. 578-85.
47. Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical
outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol
Hepatol, 2006. 4(10): p. 1248-54.
48. Afif W, Loftus EV, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-
chimeric antibody concentrations in patients with inflammatory bowel disease. Am J
Gastroenterol, 2010. 105(5): p. 1133-9.

t
49. Dassopoulos T, Cohen RD, Scherl EJ, et al. Ulcerative Colitis Care Pathway. Gastroenterology,

ip
2015. 149(1): p. 238-45.
50. Sandborn WJ. Crohn's disease evaluation and treatment: clinical decision tool. Gastroenterology,
2014. 147(3): p. 702-5.

cr
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

51. Feuerstein JD, Nguyen GC, Kupfer SS, et al. Therapeutic Drug Monitoring in Inflammatory Bowel
Disease. Gastroenterology, 2017.
52. Roda G, Jharap B, Neeraj N, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and

us
Management. Clin Transl Gastroenterol, 2016. 7: p. e135.
53. Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab
therapy eliminates antidrug antibodies in serum and restores clinical response of patients with
an
inflammatory bowel disease. Clin Gastroenterol Hepatol, 2013. 11(4): p. 444-7.
54. Ong DE, Kamm MA, Hartono JL, et al. Addition of thiopurines can recapture response in patients
with Crohn's disease who have lost response to anti-tumor necrosis factor monotherapy. J
Gastroenterol Hepatol, 2013. 28(10): p. 1595-9.
M
55. Roblin X, Danese S, and Peyrin-Biroulet L. Does anti-TNF therapy cost so many COINs?
Gastroenterology, 2014. 146(1): p. 309-11.
56. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to
infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol
ed

Hepatol, 2004. 2(7): p. 542-53.

57. Baert F, Norman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of
infliximab in Crohn's disease. N Engl J Med, 2003. 348(7): p. 601-8.
58. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive
pt

therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut, 2007.
56(9): p. 1226-31.
59. Seow CH, Newman A, Irwin SP, et al. Trough serum infliximab: a predictive factor of clinical
ce

outcome for infliximab treatment in acute ulcerative colitis. Gut, 2010. 59(1): p. 49-54.
60. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, et al. Proactive therapeutic concentration
monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease:
results from a pilot observational study. Inflamm Bowel Dis, 2014. 20(11): p. 1996-2003.
Ac

61. Papamichael K, Chachu KA, Vajravelu RK, et al. Improved Long-term Outcomes of Patients With
Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum
Concentrations of Infliximab. Clin Gastroenterol Hepatol, 2017.
62. Vande Casteele N and Gils A, Preemptive Dose Optimization Using Therapeutic Drug Monitoring
for Biologic Therapy of Crohn's Disease: Avoiding Failure While Lowering Costs? Dig Dis Sci, 2015.
60(9): p. 2571-3.

23
 Table 1. Risk Factors for Primary Non-Response to Infliximab

Male gender [15]

High body mass index [15]

High C reactive protein [20]

t
ip
High TNF level [16]

cr
High IL-8 level [9]
Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

High TNF:CRP ratio [9]

us
Low serum albumin [9] an
Complicated Crohn’s disease

Deep ulcerations on endoscopy [15]

M
Smoking [10]

Small bowel involvement [10]

ed

Disease duration greater than 2 years [10]

FAS-L mutation [10]

pt

Caspase-9 mutation [10]

ce
Ac

24
 Downloaded by [UC Santa Barbara Library] at 07:07 07 September 2017

Ac
ce
pt
ed

25
M
an
us
cr
ip
t