Review article: causative factors and the clinical management of patients with Crohn’s disease who...

For Peer Review

Review article: Causative factors and clinical management of patients with Crohn’s disease who lose response to anti-

TNFφ therapeutics

Journal: Alimentary Pharmacology & Therapeutics

Manuscript ID: APT-0421-2010.R3

Wiley - Manuscript type: Review Article

Date Submitted by the Author:

11-Apr-2011

Complete List of Authors: Danese, Silvio; Istituto Clinico Humanitas, Gastroenterology Fiorino, Gionata; Policlinico Umberto I, GI Unit, Dipartimento Scienze Cliniche Reinisch, Walter; Univ.-Klinik Innere Medizin IV, Gastroenterologie

Keywords: Crohn’s disease < Disease-based, Enteric infections < Disease-based, Inflammatory bowel disease < Disease-based, Ulcerative colitis < Disease-based

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Author manuscript, published in "Alimentary Pharmacology & Therapeutics 34, 1 (2011) 1" DOI : 10.1111/j.1365-2036.2011.04679.x

http://dx.doi.org/10.1111/j.1365-2036.2011.04679.x

http://peer.ccsd.cnrs.fr/peer-00637818/fr/

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Review article: Causative factors and clinical management of patients with Crohn’s Review article: Causative factors and clinical management of patients with Crohn’s Review article: Causative factors and clinical management of patients with Crohn’s Review article: Causative factors and clinical management of patients with Crohn’s disease who lodisease who lodisease who lodisease who looooose response to se response to se response to se response to anti TNFanti TNFanti TNFanti TNF----α α α α therapy therapy therapy therapy

Silvio Danese1, Gionata Fiorino1, Walter Reinisch2* 1 IBD Unit, IBD Center, Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy 2Universitätsklinik Innere Medizin III, Abteilung Gastroenterologie und Hepatologie

Corresponding Author:Corresponding Author:Corresponding Author:Corresponding Author: Walter Reinisch, Vienna, Austria. E-mail: [email protected], Telephone: +43 1 40400 4741, Fax: +43 1 40400 4735. Short Title:Short Title:Short Title:Short Title: Loss of response to anti-TNFs in Crohn's disease Key wordsKey wordsKey wordsKey words: Anti-TNF, Crohn's disease, inflammatory bowel disease, loss of response

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AbstractAbstractAbstractAbstract BACKGROUND: The addition of anti-tumour necrosis factor-(TNF)α agents to the therapeutic

armamentarium against Crohn’s disease (CD) has been a revolution in its management. However,

approximately 25 to 40% of patients who initially benefit from anti TNF-α treatment develop

intolerable adverse events or loose their response during maintenance therapy. AIM: To summarize

the current knowledge on the mechanisms underlying loss of response (LoR) in these patients, and

the therapeutic strategies available to counteract this clinical challenge. METHOD: A literature

search using PubMed, MedLine and Embase databases has been performed. RESULTS: Anti-

infliximab antibodies (ATI) formation and autoantibodies (ANA, anti-DNA and other autoantibodies)

have been associated with LoR. Individual differences in drug metabolism may contribute to LoR.

Smoking may be a risk factor for LoR. Dose escalation, reduction of infusion intervals and switch to

other anti TNF-α agents are effective as rescue strategy. CONCLUSION: LoR appears to result from

different causes not fully established by now. Optimization of therapies, or switch to other anti TNF-

α are currently the best studied strategies in case of LoR and can be successful in 40-60% of patients

who lost response.

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IntroductionIntroductionIntroductionIntroduction

Tumor necrosis factor α (TNF-α) is a key cytokine in the inflammatory process. Anti TNF-α

agents have revolutionized the treatment of patients with chronic inflammatory diseases such as

Crohn’s disease (CD), achieving better outcomes for patients than previously obtained with

conventional drugs, such as mesalazine, steroids or thiopurines. Anti TNF-α agents effectively

induce and maintain long-term remission in patients with CD 1. In addition, efficacy has been

demonstrated for the treatment of patients with ulcerative colitis (UC), the other major entity of

inflammatory bowel disease (IBD) 2.

Thus far, two anti TNF-α antibodies have been approved in the EU for the treatment of

moderately to severely active CD in patients who have not responded to a corticosteroid and/or an

immunosuppressant, or who are intolerant to or have medical contraindications for the standard

therapeutics: infliximab, a chimeric monoclonal antibody, and adalimumab, a fully humanised

monoclonal antibody. In the US, additionally a pegylated Fab' fragment of a humanised TNF

inhibitor monoclonal antibody, certolizumab pegol, has been approved for administration to patients

with CD who have not responded adequately to standard therapeutics 3.

In randomised controlled trials between 25 and 40% of patients who initially benefit from

treatment with an anti-TNF-α agent then went on to develop intolerable adverse events or were

losing their response during the scheduled maintenance treatment 4-7. The latter mostly occurred

within the first 6 months after initiation of treatment. These secondary non-responders should be

differentiated from primary non-responders, a subset of patients who do not respond to the initial

induction therapy with an anti TNF-α therapy. The reasons underlying loss-of-response are not

completely understood. The contribution of several factors have been investigated thus far, including

the development of neutralizing antibodies, the immune status of the patient, genetic factors,

alterations in metabolism of the drug, and concomitant medications that may interact with the

activity of anti-TNF-α antibodies.


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In this review, we discuss the reasons underlying this secondary LoR, as well as the

treatment options available for such patients. This review summarises currently available data on

loss-of-response to anti TNF-α therapy, and investigates possible underlying mechanisms.

MethodsMethodsMethodsMethods

A literature review was performed by searching for the terms ‘loss of response’, ‘infliximab’,

‘adalimumab’, ‘certolizumab’, ‘anti TNF-α’, ‘biologics’, combined with ‘Crohn’s disease’, ‘ulcerative

colitis’, AND lose OR lost OR loss OR “ dose escalation ” OR intensification in the PubMed, Medline,

Cochrane and EMBASE databases. All relevant articles in English published until December 2009

were reviewed.

ResultsResultsResultsResults

INCIDENCE OF LORINCIDENCE OF LORINCIDENCE OF LORINCIDENCE OF LOR

Infliximab has been used since more than one decade, and evidence strongly supports the

importance for long-term scheduled regimen. In the past, infliximab was often used episodically or

stopped after a short course of therapy 2, 8. Recently, new evidence on long-term safety of infliximab

and adalimumab as well as the benefit to treat patients who were in remission after a year of

treatment has changed our clinical practice towards long-term use 9, 10. On the other hand, scheduled

treatment regimens with infliximab and adalimumab are associated with an increased incidence of

LoR. In fact, this event is estimated to account for 13% of patients/year under scheduled treatment

11, although the incidence varies markedly in different studies. Several predictors for LOR have been

suggested, although reproducibly still remains to be determined.

MECHANISMS OF LORMECHANISMS OF LORMECHANISMS OF LORMECHANISMS OF LOR

AntiAntiAntiAnti----infliximab antibodiesinfliximab antibodiesinfliximab antibodiesinfliximab antibodies.

The mechanisms underlying LoR to an anti-TNF-α therapy by patients with CD are poorly

understood. This limitation has prevented the delineation of robust strategies to manage this clinical

challenge. However, reviewing the currently available literature indicates that several mechanisms


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are involved in the process of LoR, although no single one of them appears to completely explain the

event. The mostly investigated process associated with LoR is the influence of immunogenicity 7. Up

to 60% of patients who are undergoing an episodic treatment regimen with infliximab develop

antibodies to infliximab (ATIs), predisposing those patients to acute infusion reactions, delayed

serum sickness-like reactions, and to a reduction in the duration of their response to treatment 7.

LoR is common under scheduled treatment as well whereas ATI formation is less frequent in this

situation, which indicates that LoR to infliximab is not solely to be explained by immunogenicity 12.

Furthermore, although episodic treatment and associated disappearance of infliximab from the

circulation appear to booster ATI formation and favour LoR, ATIs are not detected in approximately

25% of patients who lack detectable serum trough levels of infliximab 13. A variety of possible

mechanisms have been postulated to underlie this observation, which are summarised in Table 1.

Residual trough serum levels of infliximab are inversely correlated with the levels of

immunoreactive TNF-α in the circulation. However, ATIs have been shown to diminish the

biologically inactivating effects of systemic infliximab 14. Indeed, the neutralizing activities exerted

by ATI appear to be linked to their serum titres: although high titres are associated with LoR and

infusion-mediated reactions, when the interval between infusions is decreased in patients with

moderate titres, some will continue to maintain remission under infliximab, which points to the

presence of circulating biologically active drug 14. Additionally, ATI impact the pharmacokinetics of

infliximab by increasing its clearance. In a study in patients with ankylosing spondylitis, the

clearance of infliximab was up to 75% greater in patients who had developed ATI compared with

patients who were ATI negative 14.

Other autoantibodiesOther autoantibodiesOther autoantibodiesOther autoantibodies

In addition to ATI, auto-antibodies can play a role in LoR to infliximab. A small prospective

study in patients with psoriasis investigated the role of antinuclear antibodies (ANA) and anti

dsDNA antibodies in patients who no longer responded to one or more of the three anti TNF-α agents

15. Patients who had lost their response to the anti-TNF-α therapeutics had high titres of ANA and


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anti dsDNA antibodies. In particular, the rate of positivity for those auto-antibodies was

proportional to the number of different anti-TNF-α therapeutics the patients were administered. Up

to 83% of patients who underwent three different anti TNF-α had positivity for those auto-

antibodies. One possible explanation for this observation is that the apoptotic effects of the drugs

may increase the exposure of nuclear material to the immune system which appears particularly

increased when coupled with low serum levels of C-reactive protein (CRP), a natural scavenger for

nuclear detritus following apoptosis 15. A prospective cohort study showed that more than 50% of

patients under prolonged therapy with infliximab develop auto-antibodies such as double-stranded

(ds) DNA, single-stranded (ss) DNA and anti-histone antibodies, and that they generally persist up

to 1 year after the last infusion 16. However, the clinical relevance of anti-nuclear antibodies remains

elusive, albeit they appear to be associated with some infusion-related disease, especially skin

disorders. In addition, ANA-positive patients have been reported to be more likely to develop

significant ATI titres compared with patients who remain ANA negative, which poses another

explanation for increased risk of LoR in ANA positive patients although not shown in the respective

study 16. More detailed studies are required to improve our understanding on how ANA and anti-

dsDNA antibodies could be involved in the induction of LoR to anti TNF-α, and as to whether the

observed associations are causatively linked or simply an epiphenomenon.

TTTTrough serum concentrationrough serum concentrationrough serum concentrationrough serum concentration

More recent studies on trough serum concentration of anti-TNF-α agents entered the focus of

interest in the research on mechanisms driving LoR. Clinical remission was achieved by 82% of

patients with CD in whom there was a detectable serum trough level of infliximab as compared to

6% of patients in whom serum infliximab was undetectable (p<0.001), including those without ATI.

In addition to improved remission rates, detectable trough levels of infliximab in the serum were also

associated with lower serum levels of CRP, and a higher rate of endoscopic improvement 17.

Similarly, in patients with UC administered infliximab, clinical remission was clearly associated

with detectable trough levels of infliximab in the serum, as was endoscopic improvement and a


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decrease in the risk of subsequent colectomy (odds ratio 9.3; 95% confidence interval, 2.9 - 29.9; P

<0.001) 18.

However, when patients are administered the standard regimen of 5 mg/kg every 8 weeks,

only 40% of patients have detectable pre-infusion trough levels of infliximab in their serum at the

scheduled therapy points,18. In addition, there is considerable inter-patient variability in the trough

concentration of serum infliximab, pointing to broad variations in individual’s clearance rates. The

standard regimen would therefore appear to be inadequate for a substantial proportion of patients.

Pharmacokinetic studies have found that higher trough serum concentrations of infliximab can be

achieved by either shortening the interval between infusions, or by increasing the dose of infliximab

19. In humans, adjusting the dose and/or the interval improves the pharmacokinetic profile of

infliximab and thereby increases the proportion of patients who maintain a long-term clinical

response 9. Recently, a retrospective study aimed to investigate whether shortening of infliximab

infusions or dose increase in patients with Crohn’s disease may have differences in rescuing response

resulted in no significant differences between strategies 20.

More recently, serum albumin levels have been revealed as predictor for infliximab

pharmacokinetics and clinical response in patients with moderately to severely active ulcerative

colitis Patients with higher serum albumin concentrations maintained higher infliximab

concentrations, lower clearance, and longer half-life than patients with lower serum albumin. These

observations are of major interest and may help to steer treatment with infliximab in ulcerative

colitis. However, a potential mechanism behind these associations and its relevance for Crohn’s

disease remains to be determined21. In patients with ankylosing spondylitis liver enzymes or

creatinine clearance do not affect the metabolism of infliximab 14. Body surface area and sex were

significant covariates to the distribution of infliximab in the central compartment. No interaction

has been found between non steroidal anti-inflammatory drugs (NSAID) or proton pump inhibitors

(PPI)14. However, a correlation between higher white blood cell count at baseline and clearance of

infliximab has been observed, probably because an activated reticular-endothelial system plays a key

role in the catabolism of therapeutic IgG 22.


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As an alternative to the measurement of serum trough levels and ATIs the role of functional

infliximab circulating in the blood has been investigated in a small study on 33 patients with Crohn’s

disease treated with infliximab 23. The authors suggested that levels of functional IFX and TNF-α-

binding capacity (TNF-α-BC) as measured by fluid-phase radioimmunoassay can better predict

primary failure of infliximab than ATI levels alone. Moreover, the infliximab concentration/ TNF-α-

BC ratio could be a useful tool to optimize therapy and to select patients for dose increase or

shortening of intervals 23. Further studies are needed to confirm this observation and on how to

make the method easily accessible to clinical practice.

Concomitant medications and metabolic factorsConcomitant medications and metabolic factorsConcomitant medications and metabolic factorsConcomitant medications and metabolic factors

Evidence is accumulating that metabolic factors, as well as particular concomitant therapies,

could influence the clearance of anti-TNF-α antibodies. In patients with rheumatoid arthritis (RA),

the elimination rate of infliximab is lower in patients who are on concomitant methotrexate 24. Thus

far, this observation has not been extended to patients with CD. On the other hand, when patients

with CD discontinue concomitant azathioprine, trough serum concentrations of infliximab are

decreasing compared to patients who continue a concomitant maintenance regimen with

azathioprine 25.

Smoking is a risk factor for relapses, surgery and need for steroids and immunosuppressants

in Crohn’s disease 26. There is increasing evidence that smoking also affects the efficacy of anti TNFs

and increases the risk of LoR. A recent study on 30 patients treated with adalimumab suggested that

smokers are significantly less likely to respond to treatment and that this effect correlates with the

number of cigarettes/day 27.

Concerning adalimumab, the induction regimen appears to impact long-term efficacy. Loftus

et al. found that patients receiving an induction regimen of 160/80 mg were half as likely to receive


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weekly dosing due to LoR compared to 80/40 regimen. Regional variation in the United States

population was also described. Sex and age did not impact on the risk of LoR 28.

The role of pharmacogenomics in biological therapy for IBD is a recent concept currently

evolving. The mechanisms of action of anti TNFs are not completely elucidated 29, and studies

concerning this particular topic are at the very early stage. In RA, van Baarsen et al. 30 found that

thousands of genes are involved in the pharmacologic response to TNF-blockers including infliximab,

adalimumab and etanercept irrespective of clinical response by investigating peripheral blood cells.

Down-regulated genes reflected several biological pathways such as inflammation, angiogenesis, B-

and T-cell activation. The same group of authors do not support the notion that microarray analysis

of pre-treatment biopsy specimens from synovia could be used in the context of personalized

medicine to identify non-responders to anti-TNF therapy. They argue with the impact of the varying

presence of lymphoid aggregates in rheumatoid synovial tissue on results from studies about gene

expression31. Nevertheless, a recent gene array study on mucosal biopsies from patients with

ulcerative colitis identified a predictive panel of genes for response to infliximab. The top five

differentially expressed genes which differentiated responders from non-responders with 95%

sensitivity and 85% specificity were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide

synthase 2, interleukin 13 receptor alpha 2 and interleukin 1132. A similar approach on patients with

Crohn’s disease allowed complete separation between colonic CD responders and non-responders.

The top 5 genes in that study were TNFAIP6, S100A8, interleukin 11, G0S2, and S100A9. A

predictive gene panel for IFX responsiveness in ileal CD could not be derived. Interestingly, there

was a huge overlap between the predictive genes identified in colonic CD and ulcerative colitis33. Of

note is another study showing that dysregulated anti-microbial peptides (AMPs) in IBD mucosa in

general normalize in responders to infliximab, suggesting that dysregulation of AMPs is rather the

consequence of inflammation than primary cause in IBD34, All the above studies need to find further

confirmation in large series but are pointing towards a direction of gene expression-based tailoring of

anti-TNF-α treatment in IBD.


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MANAGEMENT OF LoRMANAGEMENT OF LoRMANAGEMENT OF LoRMANAGEMENT OF LoR

PreventionPreventionPreventionPrevention

Some prevention strategies have been investigated to reduce the risk of LoR in scheduled

maintenance therapy with infliximab. Combination with steroids and immunosuppressants can help

to reduce ATI formation, but data are contrasting and currently do not allow clear indications.

Premedication with hydrocortisone has been studied in a prospective randomized placebo-

controlled trial in 53 patients, showing that it can be useful in reducing ATI formation, although it

does neither eliminate ATI formation nor infusion reactions 35. The use of concomitant

azathioprine/6-mercaptopurine or methotrexate has been also shown to reduce ATI formation

significantly 36. Recently, pre-medication with hydrocortisone has been compared to the concomitant

use of azathioprine, however, no significant differences between both strategies in reducing the risk

of LoR could be shown.37 Whereas, van Assche et al. could not reveal differences in terms of LoR in

patients who discontinued or continued azathioprine after 6 months of combined therapy infliximab-

azathioprine 25, Oussalah et. al. harvested different results 38. In the latter study withdrawal of

azathioprine during combined azathioprine-infliximab treatment before 27 months as well as the

presence of signs of biological inflammation were found to be predictive for further loss of response to

infliximab monotherapy. Indeed, in a large-scale clinical trial, SONIC (the Study of Biological and

Immunomodulator Naïve Patients with CD), a higher proportion of patients remained in steroid-free

remission in the combination arm of infliximab plus azathioprine compared with patients who were

on infliximab alone 39. Whether this results from a negative effect of azathioprine on clearance of

infliximab, a less immunogenic environment as a result of the combination therapy, or is simply due

to a bias resulting from an uneven distribution of patients with objective signs of inflammation at

baseline, remains to be clarified 39. At the moment, it seems that concomitant immunosuppression is

the best strategy to increase therapeutic efficacy and reduce the risk of LoR.

Dose adjustDose adjustDose adjustDose adjustmentmentmentment and switching to other anti TNF and switching to other anti TNF and switching to other anti TNF and switching to other anti TNF


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Pharmacokinetic studies and randomized controlled trials on infliximab suggest that a dose

increase up to 10 mg/kg or shortening the intervals between infusions at 4 or 6 weeks can be an

effective strategy to rescue response after LoR 8, 9, 20. Different strategies seem to be not significantly

different, therefore infliximab can be administered at 5 mg/kg every 4 or 6 weeks, or at dose of 10

mg/kg every 8 weeks 20. Although neither adalimumab nor certolizumab pegol appear to be as

immunogenic as infliximab, nonetheless patients administered these therapeutics demonstrate a

similar frequency of LoR during maintenance therapy compared with patients administered

infliximab. Despite differences in chemical structure that should reduce immunogenicity, the use of

adalimumab can also lead to formation of anti-adalimumab antibodies (AAA) and to the decrease of

trough serum levels, similarly to infliximab 40. This formation is also associated with LoR, suggesting

that immunogenicity seems not to depend solely upon the chimeric structure of infliximab, and

supports the concept that the underlying mechanism is related to inter-individual variations in drug

clearance rather than immunogenicity 5, 6. When patients lose response to adalimumab, escalation of

their dose to weekly instead of every 2 weeks (40 mg, subcutaneously) restores the response, with a

drop in the CD activity index (CDAI) of > 70 occurring in 76% of patients, and 45% of patients

entering remission (CDAI < 150) 41. Dose escalation also rescues response in patients administered

400 mg certolizumab pegol subcutaneously, with the dosing frequency being increased from every 4

to every 2 weeks. In the non-controlled PRECiSE 4 clinical trial, this re-induction strategy resulted

in a 28.6% remission rate in patients who had lost their response to certolizumab pegol during

maintenance treatment, which was stable throughout a follow-up period of 12 months 42, 43. In

summary a substantial proportion of patients who stop responding to first line anti-TNF-α treatment

regain response after a dose intensification strategy with the same agent is implemented either by

involving a reduction in interval or an increase in dose. A dose intensification strategy should

therefore be considered prior to switching the patient to another agent (Figure 1). Indeed, dose

escalation yields more quality-adjusted life-years than switching, although the costs associated with

this approach seem to be higher 44.


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On the other hand, switching to an alternative anti-TNF-α drug is also an effective strategy,

and currently considered to pose the first treatment option in patients intolerant of their primary

anti-TNF-α therapy. Indeed, a switch to a secondary anti-TNF-α antibody appears warranted even

after futile dose adjustments of the primary anti-TNF-α compound have been attempted. Given that

infliximab has been on the market for a significantly longer time than either adalimumab or

certolizumab pegol, it is not surprising that the majority of the available data involves patients who

have lost their response to infliximab, and who were subsequently switched to one of the other two

anti-TNF-α therapeutics. Post hoc analyses of trials involving patients who were intolerant of or

losing response to infliximab and were subsequently enrolled into maintenance studies with

adalimumab and certolizumab pegol indicate that a lower proportion of patients respond to the

second-line anti TNF-α therapy compared with patients naïve to anti-TNF-α therapeutics 5, 6.

Thus far only one randomised, double-blind, placebo-controlled trial has reported on the

efficacy of a second line anti-TNF-α agent in patients who were intolerant of or lost response to a

first line anti-TNF-α agent. The GAIN (Gauging Adalimumab Efficacy in Infliximab Non-

Responders) trial found that adalimumab (160 mg at week 0 followed by 80 mg at week 2) induced

remission at week 4 in 21% of infliximab non-responders with moderate to severe CD compared with

7% of patients administered placebo (p < 0.001) 45. This rate of remission was lower than the

response rate reported for patients’ naïve to biological agents. In the CLASSIC I clinical trial 36% of

patients previously not exposed to biologics achieved remission at week 4 with an induction regimen

of adalimumab 160 mg at week 0 followed by 80 mg at week 2 46.

More support for switching to a second anti-TNF-α agent came from a systematic review of

15 studies, which identified 1810 patients who had discontinued infliximab and switched to

adalimumab 47. Remission rates were highly variable across the 15 different studies, with short-term

rates of between 41 and 83%, and rates of 19 to 68% at 12 months. Nonetheless, overall adalimumab

was found to be effective in patients who have lost response to or were intolerant of infliximab 47.

Recently, Afif et al. have showed that measurement of Human Anti-Chimeric Antibodies (HACAs)

can be useful to select patients who need directly a switch from infliximab to adalimumab without


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passing through dose escalation or interval reduction. In fact, they found that 23% of patients (35

patients on 150) resulted positive to HACAs. In those patients, switching directly to adalimumab

was associated with a complete or partial response in 92% of patients, whereas dose escalation had a

response of 17%. On the other hand, in patients with subtherapeutic infliximab concentrations

negative for HACAs, dose escalation was associated with complete or partial clinical response in 86%

of patients whereas changing to another anti-TNF agent had a response of 33%48. This study shows

that measurement of HACA together with serum levels of IFX, when available, may give very useful

additional information in order to make the best therapeutic choice in case of LoR.

The long-term clinical benefits of adalimumab in infliximab non-responders were assessed in

an observational study 40. Long-term clinical benefit was observed in 61.5% of patients for a median

follow-up period of 20.4 months. However, the dose was stepped up to 40 mg/week in 65.4% of

patients to maintain response, while 38.5% of the patients ceased therapy with adalimumab, mainly

due to LoR. Importantly, patients who discontinued therapy had significantly lower trough serum

concentrations than patients in whom the therapy was effective. Trough serum concentration was

also affected by antibodies against adalimumab in 9.2% of the patients 40. This effect of antibodies to

adalimumab mirrors the effects seen with ATI, and is therefore an important indication of the

similarity of the mechanisms at play in non-responders. Thus, variations in clearance of adalimumab

also appeared to be affected by immunogenicity.

Similar data have been obtained with certolizumab pegol from an open-label induction part

of a clinical trial. Patients with moderately-to-severely active CD who had failed infliximab were

administered certolizumab pegol (400 mg every 2 weeks) as a second-line treatment in the

WELCOME (26-Week trial Evaluating the clinical benefit and tolerability of certoLizumab pegol

induCtiOn and Maintenance in patients suffering from Crohn's disease with prior LoR or

intolErance to infliximab) trial. At week 6, 61.0% of patients had achieved a clinical response

(decrease in CDAI score > 100 points) and 39% had entered remission 49.

In clinical routine there is a subset of patients with CD who have received already all three

of the anti TNF- α agents as part of their overall treatment. A retrospective study identified 67


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patients of those, 27 of whom had received adalimumab as their third-line treatment and in another

40 for whom certolizumab pegol was their last-line anti TNF-α treatment after failing infliximab and

adalimumab. A clinical response was observed in 41 (61%) patients at week 6 and in 34 patients

(51%) at week 20. The probability that treatment was ongoing at 3 months, 6 months and 9 months

was 68%, 60% and 45%, respectively 50. This study suggests that administration of a third anti TNF-

α therapy should be considered if there are no alternative therapy options remaining.

The second-line indication of the anti TNF-α therapeutics may result in a situation where

these agents are being prescribed earlier and more progressively in patients with CD, even prior to

utilization of immunosuppressants. Indeed, it may not be long before we start to see patients who

have failed to respond to or have become intolerant of an anti TNF-α therapy being scheduled

maintenance therapies without previous exposure to immunosuppressants. Although such scenarios

have not yet been investigated, it seems likely that thiopurines and/or methotrexate will be an

appropriate subsequent treatment option.

Further non anti TNFFurther non anti TNFFurther non anti TNFFurther non anti TNF----α therapiesα therapiesα therapiesα therapies

The availability of biological therapeutics targeting alternate pathways than TNF-α is

limited in IBD. Natalizumab is a humanised IgG4 monoclonal antibody that targets the α4 integrin,

thereby blocking adhesion of leukocytes and their subsequent migration into the gut 1. It has been

approved for the treatment of patients with CD in the US, but not in Europe. However, in the US

natalizumab is only available through a restricted prescribing program termed CD-TOUCH due to

the risk of progressive multifocal leukoencephalopathy. The efficacy of natalizumab in patients who

have previously failed to respond to an anti TNF-α therapy has been investigated in a post hoc

analysis of data from the ENACT (Evaluation of Natalizumab as Active Crohn’s Therapy) series of

clinical trials. This analysis demonstrated that natalizumab poses a valid and efficacious treatment

option in such patients 51.

Ustekinumab is a human interleukin 12/23 monoclonal antibody. A placebo-controlled

randomized study in patients with moderately-to-severely active CD showed that ustekinumab

resulted superior to placebo at week 4 (p=0.02), but not at week 8. However, in patients previously


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treated with infliximab the response rate to ustekinumab remained significantly higher than placebo

through week 8 (p<0.05)52. Data from a large prospective randomized placebo-controlled phase II and

III trial on ustekinumab in patients with previous primary or secondary failure to anti TNFs will

provide further insights 53.

Finally, the safety and efficacy of extracorporeal photopheresis has been investigated in a

prospective, uncontrolled pilot study involving 28 patients with moderate-to-severe CD who were

refractory to or intolerant of immunosuppressants and/or anti TNF-α medications. After 12 weeks,

50% of the patients had responded to the treatment and 25% had entered remission. Of particular

interest, the response was similar among patients who were naïve to anti-TNF agents and patients

who had previously been refractory to or were intolerant of an anti TNF-α therapy 54.

DiscussionDiscussionDiscussionDiscussion

Patients who are undergoing maintenance treatment with an anti TNF-α agent frequently

lose their response during standard maintenance regimens. This largely appears to occur as a result

of inter-individual variations in the pharmacokinetics of the agents. Optimisation of the dose

administered, with particular regard to serum trough levels and functional circulating infliximab

levels successfully restores response in the majority of patients and is therefore the option of choice,

prior to considering switching to a second or third-line anti TNFα therapy.

The serum levels of ATI have been proposed as a predictive factor for LoR. However, this is

not a widely accepted hypothesis, and their predictive potential needs to be confirmed in large scale

clinical trials. The role of other auto-antibodies, such as ANA, dsDNA, ssDNA, anti-histone

antibodies and other influencing factors are still to be investigated. Further studies on the role of

activated genes in course of anti TNF therapies are needed in order to select patients who would

maintain prolonged response and to act with more effective therapeutic modifications in those who

would be likely not to respond or lose response.

Concomitant medications may help in reducing the risk of LoR, but their efficacy seems to be

limited overtime. For infliximab, thiopurines should be associated at least for 6 months, also in order


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to increase efficacy 25, 36, 39, although this could most likely only impact on ATI-derived LoR.

Furthermore, the optimum timing of combining infliximab and thiopurines remains to be

determined. More, patients should be strongly invited to quit smoking, generally as soon as they

start any therapy for CD, and not only before starting with infliximab. Concerning adalimumab and

certolizumab pegol evidence is needed to advise mono- versus combination therapy with

immunosuppressants. For adalimumab evidence accumulates that the 160/80 induction regimen is

preferable to reduce the risk of LoR.

Finally, in situations where a patient is no longer responding to a first-line anti TNF-α

therapy, it is essential that the clinician carefully re-evaluate objective signs of inflammation prior to

making any further treatment decisions. Deterioration of clinical symptoms while undergoing a

maintenance therapy regimen can occur as a result of many factors unrelated to the

pharmacodynamics of the agent, including non-inflammatory intestinal impairments such as

bacterial overgrowth, secondary lactose malabsorption, chologenic diarrhoea, steatorrhoea, and drug-

induced adverse events. In addition, the presence of complications that would merit surgical

intervention, including the formation of enteric fistulas and strictures, must be assessed. It is

important also to wait at least 12 weeks from the start of anti TNF in order to evaluate eventual

primary failures to therapy 3.

LoR is an emerging challenge in the biological era, especially because no other valid

therapeutic weapons are currently available in complicated moderate-to-severe disease, except for

steroids. Data are still limited and further prospective trials on large populations of patients are

strongly required. Optimizing the available medications in order to prolong their use as long as

possible and save further medical options is currently the best strategy to recommend in our clinical

practice.


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39. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362362362362(15):1383-1395. 40. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology 2009;137137137137(5):1628-1640. 41. Sandborn WJ, Colombel JF, Schreiber S, et al. Dosage adjustment during long-term adalimumab treatment for Crohn's disease: Clinical efficacy and pharmacoeconomics. Inflamm Bowel Dis 2011;17171717(1):141-151. 42. Sandborn WJ, Schreiber S, Hanauer SB, et al. Reinduction with certolizumab pegol in patients with relapsed Crohn's disease: results from the PRECiSE 4 Study. Clin Gastroenterol Hepatol 2010;8888(8):696-702. 43. Lichtenstein GR, Thomsen OØ, Schreiber S, et al. Continuous therapy with certolizumab pegol maintains remission of patients with Crohn's disease for up to 18 months. Clin Gastroenterol Hepatol 2010;8888(7):600-609. 44. Kaplan GG, Hur C, Korzenik J, Sands BE. Infliximab dose escalation vs. initiation of adalimumab for loss of response in Crohn's disease: a cost-effectiveness analysis. Aliment Pharmacol Ther 2007;26262626(11-12):1509-1520. 45. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146146146146(12):829-838. 46. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology 2006;130130130130(2):323-333. 47. Ma C, Panaccione R, Heitman SJ, et al. Systematic review: the short-term and long-term efficacy of adalimumab following discontinuation of infliximab. Aliment Pharmacol Ther 2009;30303030(10):977-986. 48. Afif W, Loftus EV Jr, 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;105105105105(5):1133-1139. 49. Sandborn WJ, Abreu MT, D'Haens G, et al. Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab. Clin Gastroenterol Hepatol 2010;8888(8):688-695. 50. Allez M, Vermeire S, Mozziconacci N, et al. The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF antibodies. Aliment Pharmacol Ther 2010;31313131(1):92-101. 51. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 2005;353353353353(18):1912-1925. 52. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 2008;135135135135(4):1130-1141. 53. http://www.clinicaltrial.gov/ct2/show/NCT00771667?term=ustekinumab+AND+Crohn&rank=1. 54. Abreu MT, von Tirpitz C, Hardi R, et al. Extracorporeal photopheresis for the treatment of refractory Crohn's disease: results of an open-label pilot study. Inflamm Bowel Dis 2009;15151515(6):829-836.


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http://www.clinicaltrial.gov/ct2/show/NCT00771667?term=ustekinumab+AND+Crohn&rank=1

http://www.clinicaltrial.gov/ct2/show/NCT00771667?term=ustekinumab+AND+Crohn&rank=1

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TablesTablesTablesTables Table 1. Factors associated with loss-of-response to anti TNF-α α α α therapy

Factor Mechanism of action Role

ATI IgG-mediated neutralization of the

anti TNF-α therapy

Probable

Augmented clearance Rapid elimination of drug from

circulation leads to serum

concentrations below its therapeutic

level

Probable

Concomitant therapies Interaction with drug metabolism Probable

High baseline WBC count Unknown Possible

Anti DNA, anti-histone

ANA

Unknown To be confirmed

Low CRP at baseline Reduced clearance of material derived

from anti TNF-α induced apoptosis

Not confirmed

Liver and renal function Action on clearance of the drug Not confirmed

Sex, age, BMI Unknown Unrelated


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Figure legendsFigure legendsFigure legendsFigure legends Management of LoR to anti-TNF treatment in CD


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Anti TNF-αααα agentInduction regimen

Response at week 12?

No

Yes

Switch to other treatment

Maintenance scheduled regimen

Loss of response?No

Yes

Continue treatment

Re-evaluation, then

• Dose escalation OR• Reduction of interval between doses OR• Dose escalation + reduction of interval

Rescue?

Continue new regimen

Yes

No

Switch to other biologic


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