- Email: [email protected]
Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?
Accepted Manuscript Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies? Ray K. Boyapati, Gwo-Tzer Ho, Jack Satsangi
PII: DOI: Reference:
S1542-3565(16)30863-1 10.1016/j.cgh.2016.09.152 YJCGH 54940
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 September 2016 Please cite this article as: Boyapati RK, Ho G-T, Satsangi J, Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.09.152. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Invited Editorial Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor
RI PT
Antagonists After Failure of These Therapies?
Ray K Boyapati1,2, Gwo-Tzer Ho1,3, Jack Satsangi3
SC
1. MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, United Kingdom
M AN U
2. Department of Gastroenterology, Monash Health, Melbourne, Australia 3. Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, United Kingdom
TE D
Correspondence: Ray K Boyapati ([email protected])
AC C
EP
All authors: no conflict of interest
ACCEPTED MANUSCRIPT Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies
Anti-tumor necrosis factor α (anti-TNF) therapy has revolutionised the treatment of Crohn’s
RI PT
disease (CD). However, primary nonresponse occurs in an estimated 13-40% of patients1 and secondary loss of response in 23%-46% of patients after 12 months2. A challenging and important aspect of anti-TNF management is therefore to avoid the development of
SC
nonresponse, and identify/manage secondary nonresponse if it occurs.
When commencing a patient on anti-TNF therapy, what can be done to reduce the risk
M AN U
of developing primary or secondary nonresponse? Smoking is the single most important environmental factor, and cessation should be a priority. Another potential strategy is to prevent the formation of antibodies to anti-TNF (anti-drug antibodies, ADA) which can accelerate drug clearance, form immune complexes and directly neutralise the drug’s ability to
TE D
inhibit TNFα. ADA is associated with low serum trough drug levels 3,4, which in turn may help predict clinical response in CD 5–7.
Could using comcominant immunosuppressants (i.e azathioprine, 6-mercaptapurine or
EP
methotrexate) help prevent the development of ADA? A meta-analysis of immunogenicity in autoimmune diseases found the use of concomitant immunosuppressants was associated with
AC C
a 74% risk reduction for ADA formation 8. In CD, studies of episodic infliximab found concominant immunosuppressant therapy to be associated with lower antibody formation and more stable drug concentrations 9–12, although this finding is more inconsistent in scheduled therapy (potentially due to circulating drug interfering with the ADA assay) 5,13,14. Early data presented in abstract form suggests low dose azathioprine may be sufficient to achieve this immunogenic benefit 15. The addition of an immunosuppressant has been suggested as a strategy to help recapture clinical response to infliximab by eliminating ADA 16.
ACCEPTED MANUSCRIPT In practice, many clinicians use combination therapy (i.e anti-TNF with immunosuppressant) for 6 - 12 months and then continue with infliximab monotherapy, a strategy based on results from a withdrawal study 17. Consistent with this approach, a recent retrospective analysis found withdrawal of the immunosuppressant after at least 6 months of
RI PT
combination therapy did not reduce trough levels of infliximab in patients with CD 12. However, it is currently unknown whether patients who are commencing anti-TNF but have previously failed thiopurine therapy could still benefit from combination therapy through reduced
SC
immunogenicity and resultant higher drug levels. In this edition of Clinical Gastroenterology and Hepatology, Bar-Yoseph and colleagues present a retrospective cohort study investigating
M AN U
the impact of past thiopurine response and current thiopurine use on ADA formation and clinical outcome in patients with CD treated with infliximab 18. Across four centres in Israel and Belgium between 2008 and 2014, the authors identified 207 CD patients treated with ≥4 scheduled infliximab infusions with serial ADA levels. Patients were divided into four groups: 1)
TE D
infliximab monotherapy and 2) infliximab-thiopurine combination therapy, which was subdivided into 2a) ‘past thiopurine failures’, 2b) ‘past thiopurine responders’ and 2c) ‘de-novo combination’ group (i.e no thiopurine use prior to infliximab). The primary endpoint of ADA
EP
detection occurred in 46.6% of the infliximab monotherapy group, 19.3% in past thiopurine responders (p=0.007), 16.1% in past thiopurine failures (p=0.007) and 21.9% in the de-novo
AC C
combination group (p=0.102). Patients were more likely to be in clinical remission in the combination groups compared to the monotherapy group (58.8% vs 40.9%, p=0.009). Hence, the authors suggest a beneficial effect of thiopurines in combination with infliximab on ADA formation, regardless of past thiopurine therapeutic effect. The study has a number of limitations, acknowledged by the authors. The retrospective nature of the study invariably limits the relevance of the reported observations, although it does offer informative ‘real life’ data. The core message of this study is driven by data from 34 patients in the past thiopurine failure group. In this group, it is unclear whether the thiopurine
ACCEPTED MANUSCRIPT was stopped and if so, what the time was between stopping thiopurine and initiating infliximab. Thiopurine metabolite levels were not reported and these would have been useful for assessment of adherence as well as clarifying whether past thopurine ‘failures’ had adequate 6-TGN levels. Furthermore, past thiopurine failure was defined as active disease despite more
RI PT
than 3 months of adequate therapy, raising the prospect of inclusion in this category of patients who did not have adequate time to reach full therapeutic effect. Notably, the
comparison group of past thiopurine responders included patients with secondary thiopurine
SC
failure (i.e disease exacerbation after a good initial response).
The measurement and reporting of ADA in this study warrants further consideration.
M AN U
Low titre ADA may be transient, with less clinical significance14,19; notably, the authors state that the “vast majority” of antibodies were persistent. Testing kits varied between the centres which meant ADA positive results were not standardised and the two centres using the antilambda assay had higher rates of ADA than the other two centers. Two of the kits used were
TE D
standard ELISA assays in which the presence of serum anti-TNF can interefere with assessment of ADA positivity (rendering such results inconclusive). The authors attempted to address these difficulties by re-analysing data with a more stringent endpoint (ADA positive
AC C
covariate.
EP
and serum infliximab level < 3mcg/mL), as well as assessing the effect of study center as a
Notwithstanding these limitations, the authors show evidence for the first time that the effect of thiopurines in combination with infliximab on ADA formation may be present regardless of past thiopurine therapeutic effect. The proportion of ADA detected in the past responder group was not different from the past failure group (19.3% vs 16.1%, Log-Rank p=0.54). It is important to note that the planned sample size for the combination groups was not reached, raising the possibility of a type II error. However, this needs to be considered
ACCEPTED MANUSCRIPT against the significant difference between each of these groups individually against the monotherapy group. The data also offer some insights into the dynamics of ADA formation. The cumulative risk of ADA development between the monotherapy and de-novo groups was not different after
RI PT
5 months of therapy (24.7% vs 21.9%). However, the curves diverged at this point with no new events in the de-novo group over the next 7 months (0%) compared to 29.9% in the
monotherapy group (p=0.024). It is interesting to speculate that this may relate to the 3 - 6
SC
months for thiopurines to reach full biological effect.
M AN U
Finally, more patients in the combination thiopurine-infliximab groups (compiled) were in clinical remission at the end of the study compared to the monotherapy group. This supports the argument that a better clinical option for patients may be for thiopurines to be reinitiated or continued at the time of commencing infliximab in CD, even without prior thiopurine response. A prospective clinical trial assessing this strategy would be very informative; of interest would
TE D
be trough anti-TNF and ADA data, a low dose immunosuppressant arm and the effect of subsequent immunosuppressant de-escalation. Until then, a strategy of combination antiTNF/immunosuppressant therapy for the first 6 – 12 months to reduce the risk of ADA
EP
formation seems appropriate for many patients. In practice, it is the combination of antibody
AC C
detection with clinical outcomes of safety and efficacy that impact on decision making.
References
1.
Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease - algorithm for practical management. Aliment Pharmacol Ther. 2015;(October):n/a - n/a. doi:10.1111/apt.13445.
2.
Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in
ACCEPTED MANUSCRIPT Crohn’s disease. Aliment Pharmacol Ther. 2011;33(9):987-995. doi:10.1111/j.13652036.2011.04612.x. 3.
Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut .
4.
RI PT
October 2014. doi:10.1136/gutjnl-2014-307883 .
Karmiris K, Paintaud G, Noman M, et al. Influence of Trough Serum Levels and
Gastroenterology. 2009;137(5):1628-1640.
5.
M AN U
doi:http://dx.doi.org/10.1053/j.gastro.2009.07.062.
SC
Immunogenicity on Long-term Outcome of Adalimumab Therapy in Crohn’s Disease.
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):1248-1254. doi:10.1016/j.cgh.2006.06.025. Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors
TE D
6.
of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharmacol Ther. 2014;40(6):620-628. doi:10.1111/apt.12869. Imaeda H, Takahashi K, Fujimoto T, et al. Clinical utility of newly developed
EP
7.
AC C
immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol. 2014;49(1):100-109. doi:10.1007/s00535-013-0803-4. 8.
Thomas SS, Borazan N, Barroso N, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. 2015;29(4):241-258. doi:10.1007/s40259-015-0134-5.
9.
Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination
ACCEPTED MANUSCRIPT therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. doi:10.1056/NEJMoa0904492. 10.
Baert F, Noman 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):601-608.
11.
RI PT
doi:10.1056/NEJMoa020888.
Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant
immunosuppressive therapy in suppressing the formation of antibodies to infliximab in
Drobne D, Bossuyt P, Breynaert C, et al. Withdrawal of Immunomodulators After Co-
M AN U
12.
SC
Crohn’s disease. Gut. 2007;56(9):1226-1231. doi:10.1136/gut.2006.099978.
treatment Does not Reduce Trough Level of Infliximab in Patients with Crohn’s Disease. Clin Gastroenterol Hepatol. 2014;13(3):514-521.e4. doi:10.1016/j.cgh.2014.07.027. 13.
Baert F, Kondragunta V, Lockton S, et al. Antibodies to adalimumab are associated with
TE D
future inflammation in Crohn’s patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial. Gut. 2016;65(7):1126-1131. doi:10.1136/gutjnl2014-307882.
Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in
EP
14.
AC C
patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63(8):12581264. doi:10.1136/gutjnl-2013-305259. 15.
Zator ZA, Regueiro M, Goldby-Reffner K, et al. Sa1961 Low-dose Concomitant Azathioprine is as Effective as High-dose Azathioprine in Preventing Immunogenicity to Infliximab. Gastroenterology. 2016;150(4):S417. doi:10.1016/S0016-5085(16)31449-4.
16.
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 inflammatory bowel disease. Clin Gastroenterol Hepatol.
ACCEPTED MANUSCRIPT 2013;11(4):444-447. doi:10.1016/j.cgh.2012.10.020. 17.
Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance:
doi:10.1053/j.gastro.2008.03.004. 18.
RI PT
a randomized trial. Gastroenterology. 2008;134(7):1861-1868.
Bar-Yoseph H, Waterman M, Almog R, et al. Prevention of Antidrug Antibody Formation to Infliximab in Crohn’s Patients With Prior Failure of Thiopurines. Clin Gastroenterol
M AN U
Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962-971.
EP
TE D
doi:10.1038/ajg.2013.12.
AC C
19.
SC
Hepatol. July 2016. doi:10.1016/j.cgh.2016.06.028.
PII: DOI: Reference:
S1542-3565(16)30863-1 10.1016/j.cgh.2016.09.152 YJCGH 54940
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 September 2016 Please cite this article as: Boyapati RK, Ho G-T, Satsangi J, Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.09.152. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Invited Editorial Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor
RI PT
Antagonists After Failure of These Therapies?
Ray K Boyapati1,2, Gwo-Tzer Ho1,3, Jack Satsangi3
SC
1. MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, United Kingdom
M AN U
2. Department of Gastroenterology, Monash Health, Melbourne, Australia 3. Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, United Kingdom
TE D
Correspondence: Ray K Boyapati ([email protected])
AC C
EP
All authors: no conflict of interest
ACCEPTED MANUSCRIPT Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies
Anti-tumor necrosis factor α (anti-TNF) therapy has revolutionised the treatment of Crohn’s
RI PT
disease (CD). However, primary nonresponse occurs in an estimated 13-40% of patients1 and secondary loss of response in 23%-46% of patients after 12 months2. A challenging and important aspect of anti-TNF management is therefore to avoid the development of
SC
nonresponse, and identify/manage secondary nonresponse if it occurs.
When commencing a patient on anti-TNF therapy, what can be done to reduce the risk
M AN U
of developing primary or secondary nonresponse? Smoking is the single most important environmental factor, and cessation should be a priority. Another potential strategy is to prevent the formation of antibodies to anti-TNF (anti-drug antibodies, ADA) which can accelerate drug clearance, form immune complexes and directly neutralise the drug’s ability to
TE D
inhibit TNFα. ADA is associated with low serum trough drug levels 3,4, which in turn may help predict clinical response in CD 5–7.
Could using comcominant immunosuppressants (i.e azathioprine, 6-mercaptapurine or
EP
methotrexate) help prevent the development of ADA? A meta-analysis of immunogenicity in autoimmune diseases found the use of concomitant immunosuppressants was associated with
AC C
a 74% risk reduction for ADA formation 8. In CD, studies of episodic infliximab found concominant immunosuppressant therapy to be associated with lower antibody formation and more stable drug concentrations 9–12, although this finding is more inconsistent in scheduled therapy (potentially due to circulating drug interfering with the ADA assay) 5,13,14. Early data presented in abstract form suggests low dose azathioprine may be sufficient to achieve this immunogenic benefit 15. The addition of an immunosuppressant has been suggested as a strategy to help recapture clinical response to infliximab by eliminating ADA 16.
ACCEPTED MANUSCRIPT In practice, many clinicians use combination therapy (i.e anti-TNF with immunosuppressant) for 6 - 12 months and then continue with infliximab monotherapy, a strategy based on results from a withdrawal study 17. Consistent with this approach, a recent retrospective analysis found withdrawal of the immunosuppressant after at least 6 months of
RI PT
combination therapy did not reduce trough levels of infliximab in patients with CD 12. However, it is currently unknown whether patients who are commencing anti-TNF but have previously failed thiopurine therapy could still benefit from combination therapy through reduced
SC
immunogenicity and resultant higher drug levels. In this edition of Clinical Gastroenterology and Hepatology, Bar-Yoseph and colleagues present a retrospective cohort study investigating
M AN U
the impact of past thiopurine response and current thiopurine use on ADA formation and clinical outcome in patients with CD treated with infliximab 18. Across four centres in Israel and Belgium between 2008 and 2014, the authors identified 207 CD patients treated with ≥4 scheduled infliximab infusions with serial ADA levels. Patients were divided into four groups: 1)
TE D
infliximab monotherapy and 2) infliximab-thiopurine combination therapy, which was subdivided into 2a) ‘past thiopurine failures’, 2b) ‘past thiopurine responders’ and 2c) ‘de-novo combination’ group (i.e no thiopurine use prior to infliximab). The primary endpoint of ADA
EP
detection occurred in 46.6% of the infliximab monotherapy group, 19.3% in past thiopurine responders (p=0.007), 16.1% in past thiopurine failures (p=0.007) and 21.9% in the de-novo
AC C
combination group (p=0.102). Patients were more likely to be in clinical remission in the combination groups compared to the monotherapy group (58.8% vs 40.9%, p=0.009). Hence, the authors suggest a beneficial effect of thiopurines in combination with infliximab on ADA formation, regardless of past thiopurine therapeutic effect. The study has a number of limitations, acknowledged by the authors. The retrospective nature of the study invariably limits the relevance of the reported observations, although it does offer informative ‘real life’ data. The core message of this study is driven by data from 34 patients in the past thiopurine failure group. In this group, it is unclear whether the thiopurine
ACCEPTED MANUSCRIPT was stopped and if so, what the time was between stopping thiopurine and initiating infliximab. Thiopurine metabolite levels were not reported and these would have been useful for assessment of adherence as well as clarifying whether past thopurine ‘failures’ had adequate 6-TGN levels. Furthermore, past thiopurine failure was defined as active disease despite more
RI PT
than 3 months of adequate therapy, raising the prospect of inclusion in this category of patients who did not have adequate time to reach full therapeutic effect. Notably, the
comparison group of past thiopurine responders included patients with secondary thiopurine
SC
failure (i.e disease exacerbation after a good initial response).
The measurement and reporting of ADA in this study warrants further consideration.
M AN U
Low titre ADA may be transient, with less clinical significance14,19; notably, the authors state that the “vast majority” of antibodies were persistent. Testing kits varied between the centres which meant ADA positive results were not standardised and the two centres using the antilambda assay had higher rates of ADA than the other two centers. Two of the kits used were
TE D
standard ELISA assays in which the presence of serum anti-TNF can interefere with assessment of ADA positivity (rendering such results inconclusive). The authors attempted to address these difficulties by re-analysing data with a more stringent endpoint (ADA positive
AC C
covariate.
EP
and serum infliximab level < 3mcg/mL), as well as assessing the effect of study center as a
Notwithstanding these limitations, the authors show evidence for the first time that the effect of thiopurines in combination with infliximab on ADA formation may be present regardless of past thiopurine therapeutic effect. The proportion of ADA detected in the past responder group was not different from the past failure group (19.3% vs 16.1%, Log-Rank p=0.54). It is important to note that the planned sample size for the combination groups was not reached, raising the possibility of a type II error. However, this needs to be considered
ACCEPTED MANUSCRIPT against the significant difference between each of these groups individually against the monotherapy group. The data also offer some insights into the dynamics of ADA formation. The cumulative risk of ADA development between the monotherapy and de-novo groups was not different after
RI PT
5 months of therapy (24.7% vs 21.9%). However, the curves diverged at this point with no new events in the de-novo group over the next 7 months (0%) compared to 29.9% in the
monotherapy group (p=0.024). It is interesting to speculate that this may relate to the 3 - 6
SC
months for thiopurines to reach full biological effect.
M AN U
Finally, more patients in the combination thiopurine-infliximab groups (compiled) were in clinical remission at the end of the study compared to the monotherapy group. This supports the argument that a better clinical option for patients may be for thiopurines to be reinitiated or continued at the time of commencing infliximab in CD, even without prior thiopurine response. A prospective clinical trial assessing this strategy would be very informative; of interest would
TE D
be trough anti-TNF and ADA data, a low dose immunosuppressant arm and the effect of subsequent immunosuppressant de-escalation. Until then, a strategy of combination antiTNF/immunosuppressant therapy for the first 6 – 12 months to reduce the risk of ADA
EP
formation seems appropriate for many patients. In practice, it is the combination of antibody
AC C
detection with clinical outcomes of safety and efficacy that impact on decision making.
References
1.
Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease - algorithm for practical management. Aliment Pharmacol Ther. 2015;(October):n/a - n/a. doi:10.1111/apt.13445.
2.
Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in
ACCEPTED MANUSCRIPT Crohn’s disease. Aliment Pharmacol Ther. 2011;33(9):987-995. doi:10.1111/j.13652036.2011.04612.x. 3.
Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut .
4.
RI PT
October 2014. doi:10.1136/gutjnl-2014-307883 .
Karmiris K, Paintaud G, Noman M, et al. Influence of Trough Serum Levels and
Gastroenterology. 2009;137(5):1628-1640.
5.
M AN U
doi:http://dx.doi.org/10.1053/j.gastro.2009.07.062.
SC
Immunogenicity on Long-term Outcome of Adalimumab Therapy in Crohn’s Disease.
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):1248-1254. doi:10.1016/j.cgh.2006.06.025. Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors
TE D
6.
of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharmacol Ther. 2014;40(6):620-628. doi:10.1111/apt.12869. Imaeda H, Takahashi K, Fujimoto T, et al. Clinical utility of newly developed
EP
7.
AC C
immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol. 2014;49(1):100-109. doi:10.1007/s00535-013-0803-4. 8.
Thomas SS, Borazan N, Barroso N, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. 2015;29(4):241-258. doi:10.1007/s40259-015-0134-5.
9.
Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination
ACCEPTED MANUSCRIPT therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. doi:10.1056/NEJMoa0904492. 10.
Baert F, Noman 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):601-608.
11.
RI PT
doi:10.1056/NEJMoa020888.
Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant
immunosuppressive therapy in suppressing the formation of antibodies to infliximab in
Drobne D, Bossuyt P, Breynaert C, et al. Withdrawal of Immunomodulators After Co-
M AN U
12.
SC
Crohn’s disease. Gut. 2007;56(9):1226-1231. doi:10.1136/gut.2006.099978.
treatment Does not Reduce Trough Level of Infliximab in Patients with Crohn’s Disease. Clin Gastroenterol Hepatol. 2014;13(3):514-521.e4. doi:10.1016/j.cgh.2014.07.027. 13.
Baert F, Kondragunta V, Lockton S, et al. Antibodies to adalimumab are associated with
TE D
future inflammation in Crohn’s patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial. Gut. 2016;65(7):1126-1131. doi:10.1136/gutjnl2014-307882.
Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in
EP
14.
AC C
patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63(8):12581264. doi:10.1136/gutjnl-2013-305259. 15.
Zator ZA, Regueiro M, Goldby-Reffner K, et al. Sa1961 Low-dose Concomitant Azathioprine is as Effective as High-dose Azathioprine in Preventing Immunogenicity to Infliximab. Gastroenterology. 2016;150(4):S417. doi:10.1016/S0016-5085(16)31449-4.
16.
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 inflammatory bowel disease. Clin Gastroenterol Hepatol.
ACCEPTED MANUSCRIPT 2013;11(4):444-447. doi:10.1016/j.cgh.2012.10.020. 17.
Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance:
doi:10.1053/j.gastro.2008.03.004. 18.
RI PT
a randomized trial. Gastroenterology. 2008;134(7):1861-1868.
Bar-Yoseph H, Waterman M, Almog R, et al. Prevention of Antidrug Antibody Formation to Infliximab in Crohn’s Patients With Prior Failure of Thiopurines. Clin Gastroenterol
M AN U
Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962-971.
EP
TE D
doi:10.1038/ajg.2013.12.
AC C
19.
SC
Hepatol. July 2016. doi:10.1016/j.cgh.2016.06.028.