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REPORT DDW 2015: New Research on Proactive Monitoring in Inflammatory Bowel Disease and on Identifying Biomarkers of Relapse Faculty Marla Dubinsky, MD Professor of Pediatrics Chief, Pediatric Gastroenterology Co-Director of the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center Icahn School of Medicine at Mount Sinai Hospital New York, New York

he search for biomarkers in inflammatory bowel disease (IBD) to monitor disease activity, predict disease progression, or monitor treatment success continues to be an active area of research, and was a key focus of various presentations at Digestive Disease Week (DDW), which took place in Washington, DC, from May 16-19, 2015. Monitoring drug concentrations and antidrug antibodies to anti–tumor necrosis factor (TNF) therapy can help explain why patients have lost response to therapy after an initial benefit, a phenomenon known as “secondary loss of response.” Algorithms suggest that loss of response due to low

drug trough concentrations can be remedied by dose intensification and that patients with antidrug antibodies can benefit by switching drugs within the same therapeutic class.1 However, these reactive recommendations do not allow for proactive dose intensification, and patients are required to fail therapy before the possible mechanism is revealed. In contrast, more recent publications support the use of proactive drug monitoring; for example, studies have shown that patients with a higher trough concentration post-induction (week 14) had better outcomes at week 54 of treatment.2,3 The TAXIT (Trough level Adapted infliXImab Treatment) trial demonstrated that proactive dose adjustment kept trough concentrations at levels between 3 and 7 U/mL, and resulted in more efficient use of the drug.4 All of these prospective studies involved infliximab, but at DDW 2015, the predictive value of adalimumab drug concentrations was also described. Previously, the POCER (Post-Operative Crohn’s Endoscopic Recurrence) study showed that adalimumab decreased endoscopic recurrence when compared with nonbiologic therapy in patients considered at highest risk for

Supported by

REPORT recurrence.5,6 The question of whether postoperative patients on adalimumab would have had a better outcome if they had higher drug concentrations has not been addressed until now. Similarly, it is unknown whether there is a minimum threshold concentration of adalimumab in the postinduction situation that predicts

better longer-term outcomes. These areas of research, along with therapeutic drug monitoring–based studies and reporting on the importance of serologic immune responses as a predictor of disease outcomes, are discussed in this review. Selected abstracts from DDW 2015 are summarized below.

A Combination of Traditional Markers of Disease Burden Is a Better Predictor of Primary Nonresponse to Infliximab In Crohn’s Disease Than Infliximab Concentrations or Anti-Infliximab Antibodies7 Billiet T, Cleynen I, Ballet V, Claes K, Princen F, Singh S, Ferrante M, Van Assche GA, Vermeire S

he value of infliximab trough levels and detection of early antibodies to infliximab for the prediction of nonresponse during the induction phase remains controversial. Additionally, the natural history of the development of early antibodies to infliximab during induction therapy has not been thoroughly characterized. To investigate the mechanisms behind primary nonresponse (PNR) to infliximab in IBD, Billiet and colleagues7 characterized the utility of serum markers of inflammation and drug levels and compared them with other factors for the purpose

■ Responders

■ Primary nonresponders

TNF, pg/mL

Week

Figure 1. Evolution of median TNF concentration (with IQR) for responders and primary nonresponders to infliximab. IQR, interquartile range; TNF, tumor necrosis factor Based on reference 7.

of predicting PNR to therapy. Within a single-center retrospective study, 201 patients with Crohn’s disease (CD) who received infliximab induction and who had not been treated with anti-TNF therapy were identified. Serum samples were obtained from these patients at 4 different time points (0, 2, 6, and 14 weeks) for measurement of albumin, antibodies to infliximab, C-reactive protein (CRP), drug trough levels, and TNF. The investigators also used the ratio of TNF to CRP as an end point to differentiate TNF-related inflammation from overall inflammation. Data were compared between responders and primary nonresponders, as defined by the complete absence of clinical improvement at week 14 according to Physician Global Assessment. Billiet and colleagues reported that PNR occurred in 16 (8%) of 201 patients, and that univariate analysis identified low albumin at week 6 as a parameter associated with PNR (P=0.01, Mann-Whitney U test). In responders, serum TNF increased after each infliximab infusion (1.6 pg/mL at week 0; 7.7 pg/mL at week 14; P<0.0001, Kruskal-Wallis test), and the increase in TNF level from week 0 to 14 was higher in responders than in nonresponders (P=0.03, Mann-Whitney U test; Figure 1). A stepwise multiple logistic regression model showed that independent and significant predictors (P<0.01) of primary response to infliximab at week 14 were albumin at week 6 (odds ratio [OR], 0.08; 95% CI, 0.02-0.37) and the TNF to CRP ratio at week 0 (OR, 3.10; 95% CI, 1.54-6.25). On the basis of these data, the investigators concluded that disease burden (indicated by the combination of low albumin, high CRP, and serum TNF) was a better predictor of PNR to infliximab than drug trough levels or the early development of anti-infliximab antibodies. Although neither TNF nor CRP level alone predicted PNR, a higher TNF to CRP ratio was predictive of PNR, which argues against the notion that PNR is mediated by mechanisms other than those related to TNF. The investigators also noted that although the study showed that serum TNF levels increased after each infliximab infusion and that this increase was higher in responders than in nonresponders, the mechanism underlying this phenomenon has not yet been determined.

REPORT Preventing Crohn’s Disease Recurrence After Resection With Adalimumab: Assessing Drug and Antidrug Antibody Levels8 Wright EK, Kamm MA, Selvaraj F, Princen F, De Cruz P, Hamilton AL, Ritchie K, Krejany EO, Gorelik A, Liew D, Prideaux L, Lawrance IC, Andrews JM, Bampton PA, Jakobovits S, Florin T, Gibson PR, Debinski H, Gearry RB, Macrae FA, Samuel D, Kronborg I, Radford-Smith GL, Selby W, Johnston MJ, Woods R, Elliott PR, Bell S, Brown SJ, Connell W, Desmond PV, Singh S

urgical resection of affected intestinal segments is sometimes indicated in patients with moderate to severe CD; however, most patients who undergo such resection typically have recurrence of disease.9 Although studies have indicated that postoperative adalimumab therapy is useful for prevention of such recurrence,10 some patients who undergo this therapy still experience recurrence for reasons that remain unclear. Investigators have noted that low anti-TNF drug concentrations and the development of anti-adalimumab antibodies might underlie the loss of response to therapy.11,12 To explore this issue, Wright and colleagues8 studied 52 patients with CD who underwent intestinal resection and received postoperative adalimumab therapy. A total of 126 serum samples were obtained from patients at 6, 12, and 18 months postoperatively for measurement of adalimumab drug levels and for assessment of anti-adalimumab antibody, CRP, and fecal calprotectin levels. Assessment of disease activity and recurrence was done via colonoscopy at 6 and/or 18 months postoperatively and with the IBD Questionnaire and CDAI. Disease recurrence was defined as a Rutgeerts score of at least i2. The investigators reported that 38% of patients had disease recurrence at 6 months and that 62% of patients had recurrence

at 18 months. However, the serum adalimumab concentrations were similar when comparing patients in remission and patients with recurrence (10 vs 8.4 mcg/mL; P=0.387). Receiver operating characteristic analysis determined that a serum adalimumab level of 9.3 mcg/mL was the optimal cutoff to indicate maintenance of remission and was associated with a sensitivity of 71%, specificity of 51%, positive predictive value of 33%, and negative predictive value of 84%. Adalimumab levels were inversely correlated with fecal calprotectin (r=–0.2; P=0.038), suggesting that higher drug levels prevent microscopic inflammation. However, there was no significant correlation between adalimumab levels and CRP or Rutgeerts score (ie, endoscopic recurrence). The prevalence of anti-adalimumab antibodies was relatively high (34% of patients on monotherapy; 13% of patients on combination therapy), and adalimumab drug levels were lower in patients with anti-adalimumab antibodies (3.6 mcg/mL) than in those without detectable anti-adalimumab antibodies (12 mcg/mL; P<0.001). The investigators interpreted the latter data to suggest that prolonged postoperative treatment with adalimumab resulted in the development of antiadalimumab antibodies, leading to loss of protective effect and subsequent disease recurrence.

Serology Panel for Prediction of Relapse After Discontinuation of Infliximab in Patients With Crohn’s Disease Achieving Clinical Remission13 Papamichael K, Claes K, de Bruyn M, Princen F, Singh S, Van Assche GA, Rutgeerts PJ, Vermeire S, Ferrante M, Hauenstein S

lthough anti-TNF therapy has revolutionized the treatment of CD, the optimal indications to stop such therapy in patients who have experienced durable remission remain unknown.14 The first step in developing such criteria is to establish an accurate system to categorize patients as to whether they are at low or high risk for recurrence after cessation of therapy. The ideal system would use nonendoscopic parameters, such as serologic factors, as a noninvasive method of risk assessment. Papamichael and colleagues13 performed a retrospective, observational, single-center study of the utility of a wound healing and repair serologic panel for the prediction of relapse in 100 patients (median age, 25 years) with well-controlled CD who subsequently discontinued infliximab therapy. The serologic

panel assessment was performed with samples taken from patients at the time of discontinuation of infliximab therapy and included measurement of serum TNF-α, amphiregulin (AREG), epiregulin, heparin-binding epidermal growth factor (EGF)-like growth factor, hepatocyte growth factor, the heregulin-β EGF domain, betacellulin, EGF, and transforming growth factor–α. A test was deemed positive if the level of a marker was higher than the third quartile of the combined sample measurements. The relapse rate over a median follow-up period of nearly 10 years was 48%. With regard to the utility of the serologic panel, receiver operator characteristic analysis failed to identify useful predictive cutoff values for the prediction of relapse after discontinuation of infliximab therapy for any of the serologic panel

REPORT components. Univariate (log rank) and multiple Cox regression analyses with data from the entire cohort showed a nonstatistically significant trend toward the ability of positive AREG to predict relapse (P=0.07). When analyzing data from the 34 patients treated mainly for luminal disease, multivariate analysis showed positive AREG, which is highly expressed only in the active inflamed, and not in the normal, mucosa of patients with CD,15 was an independent predictor of relapse after

discontinuation of infliximab therapy (hazard ratio, 8.1; 95% CI, 1.7-38.1; P=0.008). Use of this marker in this subgroup was associated with a sensitivity of 80%, specificity of 52%, positive predictive value of 22%, and negative predictive value of 94%. On the basis of these data, the investigators concluded that AREG titers might be useful for relapse risk stratification when considering discontinuation of infliximab, and suggested that further research is warranted.

Serum Adalimumab Serum Levels Correlate With Remission After the Induction Phase in Crohn’s Disease16 Chaparro M, Guerra I, Iborra M, Cabriada Nuño JL, Bujanda L, Taxonera C, García-Sánchez V, MarínJiménez I, Barreiro-de Acosta M, Vera I, Martín Arranz MD, Hernández-Breijo B, Mesonero F, Sempere L, Ber Nieto Y, Hinojosa J, Ramas M, Bermejo F, Beltrán B, Rodriguez-Lago I, Banales J, Mendoza JL, AguilarMelero P, Menchén L, Ferreiro R, Blazquez Gómez I, Benitez García B, Guijarro L, Linares PM, Gisbert JP

o determine whether adalimumab trough levels correlate with the rate of clinical remission in patients with CD, Chapparo and colleagues16 studied 22 patients with active disease (CDAI >150) who had not previously been treated with anti-TNF therapy. Patients were given adalimumab (160 and 80 mg at weeks 0 and 2, respectively, and then 40 mg every 2 weeks) and assessed via interview, physical examination, and blood testing at weeks 4, 8, and 14. Remission was defined as CDAI less than 150, and response to therapy was defined as a greater than 70-point decrease in CDAI after 14 weeks of treatment. After 14 weeks of therapy, 80% of patients experienced remission, 10% experienced partial response, and the

remaining 10% were nonresponders. Patient age was younger for those achieving remission (37 years) than for those who did not achieve remission (54 years; P=0.03). Further, the adalimumab trough level at weeks 4, 8, and 14 was higher for patients who achieved remission after 14 weeks of therapy than for those who did not achieve remission, although only the difference at week 8 was statistically significant. Receiver operating characteristic analysis identified the optimal adalimumab trough level cutoffs at each time point (Figure 2). The investigators concluded that higher adalimumab trough levels during the induction phase correlated with a higher rate of response and remission at 14 weeks.

Serologic Antibodies Can Predict Postoperative Recurrence Of Crohn’s Disease17 Hamilton AL, Kamm MA, Selvaraj F, Princen F, De Cruz P, Wright EK, Ritchie KJ, Krejany EO, Gorelik A, Liew D, Prideaux L, Lawrance IC, Andrews JM, Bampton PA, Sparrow M, Florin T, Gibson PR, Debinski H, Gearry RB, Macrae FA, Leong RW, Kronborg I, Radford-Smith GL, Selby W, Johnston MJ, Woods R, Elliott PR, Bell S, Brown SJ, Connell W, Desmond PV, Singh S

ost patients undergoing surgical intestinal segment resection for moderate to severe CD ultimately experience disease recurrence, and the majority of patients with such recurrence need further surgery.9 Although clinical risk factors are modestly helpful in stratifying patients in terms of their risk for relapse,18 an accurate and noninvasive serologic test that could predict recurrence with a high degree of accuracy would be beneficial. As part of the POCER study, Hamilton and colleagues17 attempted to identify serologic antimicrobial antibodies that could predict postoperative recurrence in 171 patients with CD. Patients were assessed by blood testing perioperatively (baseline) and 6 and 18 months postoperatively for antineutrophil cytoplasmic antibody (ANCA); pANCA; anti– Saccharomyces cerevisiae antibodies (ASCA-immunoglobulin [Ig]A/IgG); antibodies to Escherichia coli outer membrane porin C (anti-OmpC); the antiflagellin antibodies

anti-CBir1, anti-A4-Fla2, and anti-FlaX; and by colonoscopy at 6 and/or 18 months postoperatively. The investigators reported that postitive anti-FlaX expression (at baseline, 6 months, and 18 months) was significantly (P<0.05) more frequent in patients with disease recurrence at 18 months than for those without recurrence. Furthermore, anti-FlaX negativity at 6 months was associated with a lower risk for recurrence at 18 months (OR, 0.38; 95% CI, 0.17-0.84; P=0.018), even when adjusted for patient and disease characteristics. By contrast, ANCA negativity at 6 months was significantly (P=0.002) associated with recurrence at 6 months. However, the total antibody titer for all antibodies did not predict recurrence. On the basis of these data, the investigators concluded that serologic screening of patients before surgery may assist in selecting patients at elevated risk for postoperative recurrence.

REPORT ■ Remission at week 14

■ Response at week 14

1.0 0.8

AUC

0.6 0.4 0.2 0.0

8 Week

Adalimumab level, mcg/mL

15 12 9 6 3 0

8 Week

D. 100

Specificity, %

100

Sensitivity, %

60 40 20

8 Week

Figure 2. (A) AUC for adalimumab trough levels to predict response/remission at week 14; (B) adalimumab threshold levels associated with response/remission at week 14; (C) sensitivity of the threshold levels; and (D) specificity of the threshold levels. AUC, area under the receiver operating characteristic curve Based on reference 16.

Serologic Markers Can Predict Crohn’s Disease Phenotype19 Choung RS, Stockfisch TP, Princen F, Maue AC, De Vroey B, Porter CK, Singh S, Leon F, Riddle MS, Murray JA, Colombel J

lthough patients with CD experience inflammationinduced bowel damage over time, some patients already have complications (eg, strictures, fistulae, and abscesses) at

the time of the initial diagnosis of CD.20 Furthermore, studies have demonstrated that in some patients CD-associated antibodies are detected long before onset of clinical symptoms.21

REPORT Therefore, as part of the ongoing PREDICTS (Proteomic Research and Discovery in CD Translational Science) study, Choung and colleagues19 attempted to identify serologic markers that could detect preclinical disease or predict which patients are at risk for developing complicated disease. Blood samples from 100 patients who were ultimately diagnosed with CD were obtained at 2, 4, and 6 years before and at diagnosis. These samples were tested for ASCA-IgA/IgG; anti-OmpC; and anti-CBir1, anti-A4-Fla2, and anti-FlaX. The relationships between CD-associated antibodies at each time point and between complicated disease (internal penetrating,

stricturing, or intestinal resection) versus uncomplicated disease were evaluated (Figure 3). Before diagnosis of CD, titers of 4 markers (ASCA-IgA, ASCA-IgG, anti-A4-Fla2, and antiFlaX) were higher in patients who ultimately had complicated disease than in those with uncomplicated disease. An increase in measures of marker accumulation (quartile sum score or marker sum) was associated with a decrease in median survival (Figure 4). On the basis of these data, the investigators concluded that the profile of serum markers that are detectable before diagnosis of CD may help predict the development of complicated disease.

■ Complicated CD (n=24)

■ Uncomplicated CD (n=76)

At diagnosis

2 y before diagnosis 80

EU/mL (Median)

70 40 30 20

60 50 40 30 20

10 0

0 ASCAIgA

ASCAIgG

AntiFla2

AntiFlaX

AntiCBir1

AntiOmpC

ASCAIgA

AntiFla2

30 25 20 15 10 5

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AntiOmpC

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AntiCBir1

AntiOmpC

30 25 20 15 10 5

0 ASCAIgA

ASCAIgG

AntiFla2

AntiFlaX

AntiCBir1

AntiOmpC

ASCAIgA

AntiIgG

AntiFla2

Figure 3. CD-associated antibodies before diagnosis according to CD phenotype. ASCA, anti–Saccharomyces cerevisiae antibodies; CD, Crohn’s disease; EU, ELISA unit; Ig, immunoglobulin; OmpC, Escherichia coli outer membrane porin C Based on reference 17.

AntiFlaX

~6 y before diagnosis

EU/mL (Median)

~4 y before diagnosis

ASCAIgG

REPORT A.

B. 150

120 a

90 b

60 30 0

>10

>16 QSS

>22

Months (Median)

150

120 b

60 30 0

>2 >3 Marker Sum

Figure 4. Survival curve analysis of time from first positive to complication. QSS, quartile sum score a

P<0.001.

P<0.0001.

Discussion Primary nonresponders to infliximab have historically been thought to be mechanistic; however, emerging data, particularly in the sick ulcerative colitis patient, suggest that rapid drug clearance may result in a “pharmacokinetic failure.” Whether higher induction doses or more frequent dosing will improve both short- and long-term outcomes in acute severe ulcerative colitis remains to be seen.22 As described in their abstract, Billiet and colleagues noted that low albumin was a predictor of PNR, and that serum TNF levels before the first induction dose may be a marker of higher disease burden and signal a need for a higher induction dose.7 This finding needs to be validated, but TNF levels before induction, perhaps even more so than CRP, may be a useful marker to help indicate the best starting dose of infliximab. In the POCER study, adalimumab concentrations were not higher in postoperative patients with endoscopic remission compared with those who had evidence of endoscopic disease in the postoperative setting. Adalimumab levels, however, did correlate with fecal calprotectin level. The authors speculate that if fecal calprotectin levels correlate more with microscopic remission than with macroscopic, then further follow-up might validate drug concentrations being predictive of longerterm outcomes. In a short-term induction study, Chaparro and colleagues observed that patients in remission at week 14 had higher adalimumab levels at week 8 than those not in remission (area under the curve, 0.75 for remission and 0.88 for response). This suggests that early proactive therapeutic drug monitoring for adalimumab may inform clinicians regarding the need for dose intensification during induction to prevent secondary loss of response. De-escalation of therapy is an important topic to physicians, payors, and patients with economics and fear of malignancy informing this discussion. The TAXIT study showed that for patients with infliximab levels greater than 7 ug/mL, de-escalation to between 3 and 7 ug/mL did not result in a

significant change in the proportion of patients in remission or in CRP level.4 Discontinuation of therapy entirely is also a key topic. The STORI (infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors) trial first showed that approximately 50% of patients who stop anti-TNF therapy flare within a 2-year period.23,24 This was similarly shown at DDW this year.24-27 Papamichael and colleagues examined whether a novel serology panel (Prometheus Laboratories Inc.) could predict which patients would relapse. In this retrospective study, they found that serum levels of AREG, a member of the EGF family, predicted relapse off medication. These preliminary findings will need to be validated in a large prospective cohort. Two of the biggest challenges clinicians face are predicting, at the time of diagnosis, which CD patients are at high risk for progressing to disease complications and predicting which patients will have postoperative disease recurrence. Serologic immune markers targeting microbial antigens have long been known to be associated with complicated CD.28-30 Moreover, ASCA was shown to be present before to disease onset in a study of Israeli army recruits.31 Using patient blood samples from the POCER study, Hamilton et al found that anti-FlaX predicted endoscopic recurrence, suggesting that the presence of serologic risk markers for recurrence may help clinicians decide which patients to treat in the postoperative setting. In one of the most exciting abstracts from this year’s DDW meeting, Choung and colleagues reported that among “healthy” US Army recruits who were eventually diagnosed with CD, the magnitude and number of serologic immune responses in patients before diagnosis were associated with a faster time course to complicated disease. Moreover, these markers were detectable even as far out as 6 years before diagnosis. These findings hint at the notion that antibodies targeting microbial antigens may be a risk marker for developing IBD, and perhaps could be a target of future prevention strategies.

REPORT References

4. Vande Casteele N, 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):2571-2573. 5. De Cruz P, Kamm MA, Hamilton AL, et al. Crohn’s disease management after intestinal resection: a randomised trial. Lancet. 2015; 385(9976):1406-1417. 6. De Cruz P, Kamm MA, Hamilton AL, et al. Adalimumab prevents postoperative Crohn’s disease recurrence, and is superior to thiopurines: early results from the POCER study. Gastroenterology. 2012; 142(5 suppl 1):S-212. 7. Billiet T, Cleynen I, Ballet V, et al. Drug concentrations and antibodies to infliximab are inferior to the impact of disease burden in primary nonresponse to infliximab in Crohn’s disease patients. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC. 8. Wright EK, Kamm MA, Selvaraj F, et al. Preventing Crohn’s disease recurrence after resection with adalimumab: assessing drug and antidrug antibody levels. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC. 9. Rutgeerts P. Protagonist: Crohn’s disease recurrence can be prevented after ileal resection. Gut. 2002;51(2):152-153.

18. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn’s disease. Ann Surg. 2000;231(1):38-45. 19. Choung RS, Stockfisch TP, Princen F, et al. Longitudinal status of serological markers predict Chron’s disease phenotype before diagnosis: a ‘PREDICTS’ study. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC. 20. Niewiadomski O, Studd C, Hair C, et al. Prospective populationbased cohort of inflammatory bowel disease in the biologics era: disease course and predictors of severity. J Gastroenterol Hepatol. 2015;30(9):1346-1353. 21. van Schaik FD, Oldenburg B, Hart AR, et al. Serological markers predict inflammatory bowel disease years before the diagnosis. Gut. 2013;62(5):683-688. 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 Hepatol. 2015;13(2):330-335. 23. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142(1):63-70. 24. Gisbert JP, Marin AC, Chaparro M. Risk of relapse after anti-TNF discontinuation in inflammatory bowel disease: a meta analysis. Gastroenterology. 2015;148(4 suppl 1):S-262.

10. Aguas M, Bastida G, Cerrillo E, et al. Adalimumab in prevention of postoperative recurrence of Crohn’s disease in high-risk patients. World J Gastroenterol. 2012;18(32):4391-4398.

25. Casanova MJ, Chaparro M, Garcia-Sanchez V, et al. Evolution after anti-TNF drug discontinuation in patients with inflammatory bowel disease (IBD): a multicenter long-term follow-up study. Gastroenterology. 2015;148(4 suppl 1):S-476.

11. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468.

26. Tanaka H, Miyakawa M, Sakemi R, et al. Endoscopic examination is necessary for deciding to discontinue infliximab in patients with refractory ulcerative colitis who have maintained clinical remission with infliximab maintenance treatment. Gastroenterology. 2015;148(4 suppl 1):S-257.

12. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol. 2011;106(4):674-684. 13. Papamichael K, Claes K, de Bruyn M, et al. Serology panel for prediction of relapse after discontinuation of infliximab in patients with Crohn’s disease achieving clinical remission. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC. 14. Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108(1):40-47; quiz 48. 15. Nishimura T, Andoh A, Inatomi O, et al. Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon. Oncol Rep. 2008;19(1):105-110. 16. Chaparro M, Guerra I, Iborra M, et al. Correlation between adalimumab serum levels and remission after the induction phase of Crohn’s disease

27. Wolf DC, Skup M, Yang H, et al. Clinical outcomes associated with switching or discontinuation of anti-TNF inhibitors for non-medical reasons. Gastroenterology. 2015;148(4 suppl 1):S-853-S-854. 28. Vasiliauskas EA, Kam LY, Karp LC, et al. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut. 2000;47(4):487-496. 29. Dubinsky MC, Kugathasan S, Mei L, et al. Increased immune reactivity predicts aggressive complicating Crohn’s disease in children. Clin Gastroenterol Hepatol. 2008;6(10):1105-1111. 30. Ferrante M, Henckaerts L, Joosens M, et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007;56(10):1394-1403. 31. Israeli E, Groto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut. 2005;54(9):1232-1236.

Disclosure: Dr. Dubinsky is a consultant for AbbVie Inc., Celgene Corporation, Janssen Pharmaceutical Companies, Pfizer Inc., Prometheus Laboratories Inc., and Takeda, Pharmaceutical Company Limited. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Prometheus, and the faculty neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. Copyright © 2015, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

ADA15022 10/15

3. Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63(11):1721-1727.

17. Hamilton AL, Kamm MA, Selvaraj F, et al. Serological antibodies for the prediction of post-operative recurrent Crohn’s disease-results from the POCER study. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC.

NOVEMBER 2015

2. Singh N, Rosenthal CJ, Melmed GY, et al. Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(10):1708-1713.

patients. Presented at: 2015 Digestive Disease Week; May 16-19, 2015; Washington, DC.

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1. 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;105(5): 1133-1139.