FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2018178851> ?p ?o ?g. }

• W2018178851 endingPage "447" @default.
• W2018178851 startingPage "444" @default.
• W2018178851 abstract "There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay–based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies. There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay–based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies. Immunogenicity of infliximab and other anti–tumor necrosis factor (TNF) drugs in inflammatory bowel disease (IBD) is an important cause for diminished clinical response, which may culminate in treatment discontinuation.1Baert 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: 601-608Crossref PubMed Scopus (1844) Google Scholar The most commonly practiced salvage therapy is dose-intensification, but the long-term efficacy of this strategy is still questionable.2Katz L. Gisbert J.P. Manoogian B. et al.Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response.Inflamm Bowel Dis. 2012; 18: 2026-2033Crossref PubMed Scopus (112) Google Scholar, 3Regueiro M. Siemanowski B. Kip K.E. et al.Infliximab dose intensification in Crohn's disease.Inflamm Bowel Dis. 2007; 13: 1093-1099Crossref PubMed Scopus (119) Google Scholar Moreover, the ability of dose-intensification to overcome loss of response owing to antidrug antibodies remains controversial.4Afif W. Loftus E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (425) Google Scholar, 5Pariente B. Pineton de Chambrun G. Krzysiek R. et al.Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 1199-1206Crossref PubMed Scopus (97) Google Scholar Switching to another anti-TNF in such patients with immunogenic loss of response has been advocated.4Afif W. Loftus E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (425) Google Scholar, 6Sandborn W.J. Rutgeerts P. Enns R. et al.Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.Ann Intern Med. 2007; 146: 829-838Crossref PubMed Scopus (844) Google Scholar However, the efficacy of switching to anti-TNF is not optimal; it hastens the exhaustion of the limited therapeutic arsenal in IBD, and it may be impractical in some patients who already failed other anti-TNFs. An altogether alternative approach to these 2 strategies could be the addition of an immunomodulator to reverse an established immune sensitization to anti-TNF. Although starting combination immunomodulator and infliximab is known to reduce the rate of development of antibodies to infliximab (ATI),7Hanauer S.B. Wagner C.L. Bala M. et al.Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease.Clin Gastroenterol Hepatol. 2004; 2: 542-553Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 8Vermeire S. Noman M. Van Assche G. et al.Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease.Gut. 2007; 56: 1226-1231Crossref PubMed Scopus (507) Google Scholar it is unknown if the post factum addition of immunomodulators also can reverse established loss of response owing to antidrug antibodies.Therefore, the aim of the present study was to describe a series of patients who developed ATIs and undetectable infliximab, in whom ATIs were eliminated and effective infliximab drug levels were restored after the addition of an immunomodulator as a co-agent with continued infliximab.MethodsPatientsThe charts of all infliximab-treated IBD patients in the period between 2009 and 2011 who had available serial infliximab and anti-infliximab antibody levels were screened for this study. Patients who developed a loss of response to infliximab (ie, secondary nonresponse) in the presence of anti-infliximab antibodies and undetectable trough levels of infliximab were identified. Of these patients, we further identified patients who were treated at this time point by the addition of immunomodulators as a co-treatment with infliximab and recorded their clinical course and serial serum infliximab/ATI results. To reduce potential technical-related pitfalls and confounding effects, we only included patients who had at least 2 consecutive measurements showing no infliximab and positive ATI before initiation of immunomodulators. Furthermore, we only included patients whose only intervention was the addition of an immunomodulator. Thus, we excluded patients who were simultaneously dose-intensified because in these patients the subsequent pharmacokinetic observations may be the result of the anti-TNF dose increase rather than the addition of an immunomodulator. This study was approved by the institutional ethics committees of Sheba and Rambam Medical Centers.DefinitionsMaintenance dosing was defined as at least one 8-week interval of infliximab infusion after the induction course. Loss of response was defined by the re-emergence of IBD symptoms coupled with a decision of the treating physician to alter the therapy, that is, to increase the dose, switch anti-TNF, add an immunomodulator, or refer the patient for Crohn's disease–related surgery.2Katz L. Gisbert J.P. Manoogian B. et al.Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response.Inflamm Bowel Dis. 2012; 18: 2026-2033Crossref PubMed Scopus (112) Google Scholar Response to intervention was defined as improvement of the symptoms as per the treating physician's judgment, coupled with a decision to continue the treatment strategy without alterations.Determining Drug, Antidrug Antibodies, and Anti–TNF Activity of SeraInfliximab and ATI levels in the serum were measured by enzyme-linked immunosorbent assay as previously described.9Ben-Horin S. Yavzori M. Katz L. et al.The immunogenic part of infliximab is the F(ab')2, but measuring antibodies to the intact infliximab molecule is more clinically useful.Gut. 2011; 60: 41-48Crossref PubMed Scopus (180) Google Scholar For assessment of anti-TNF activity, exogenous human recombinant TNF (PeproTech, Rocky Hill, NJ) was added in graded concentrations and was pre-incubated for 60 minutes at room temperature with thawed sera of patients obtained at the time of loss of response and at 3 months after initiation of concomitant immunomodulator. After preincubation, free TNF content in serum was measured by enzyme-linked immunosorbent assay for human TNF (R&D, Minneapolis, MN), as per the manufacturer's instructions, and results were expressed as optical density.ResultsFive patients with loss of response to infliximab in the presence of ATI and undetectable infliximab levels have received concomitant immunomodulator as an adjunct treatment to infliximab. The clinical characteristics of these patients are shown in Table 1. All patients except one were treated with infliximab monotherapy at the time loss of response evolved, and in all patients absent trough levels of the drug and detectable ATIs were determined in sera obtained at the time of loss of response. The titers of trough levels of ATIs, which previously were increased persistently on consecutive infusions, decreased over subsequent infusions and disappeared 1 to 5 months after the addition of an immunomodulator in all patients. This is shown for 2 exemplary patients in Figure 1A. Strikingly, this ATI decrease was accompanied by a reappearance of measurable trough infliximab levels that were evident during repeated subsequent infusions, thereby indicating a stable rather than a transient phenomenon (Figure 1A). Importantly, this was coupled with restoration of clinical response in all patients.Table 1Clinical Characteristics of the Study PopulationPatient numberSex, ageDisease phenotype, location, and duration, yPrior treatmentsNumber of infusions until LOR, Dose at LOREvidence of active inflammation at loss of responseImmunomodulator introducedSubsequent course1M, 26Inflammatory CD, small bowel and perianal, 8 yAzathioprine, methotrexate, adalimumab5 infusions, 5 mg/kg/6 wkCRP ×7 ULNMethotrexateCRP level normalized, clinical remission 12 mo, dose reduced to 5 mg/kg/8 wk2F, 18Inflammatory CD, small bowel and upper GI CD, 3 yAzathioprine, methotrexate7 infusions 5 mg/kg/4 wkCRP ×4 ULN6-MPCRP level normalized, clinical remission 10 mo3M, 22Inflammatory CD, small bowel and perianal, 2 yNone14 infusions, 5 mg/kg/4 wkFistula dischargeAzathioprineClinical response, 8 mo, dose reduced to 5 mg/kg/6 wk4M, 37Left-sided UC, 2 yAzathioprine9 infusions, 5 mg/kg/6 wkCRP ×10 ULN Active colitisAzathioprineClinical remission 13 mo5F, 34Left-sided UC, 3 yAzathioprine3 infusions, induction regimenSevere active colitis on endoscopyMethotrexateNormal CRP level, clinical remission 10 moCD, Crohn's disease; CRP, C reactive protein; F, female; GI, gastrointestinal; LOR, loss of response; M, male; 6-MP, 6-mercaptopurine; UC, ulcerative colitis; ULN, upper limit of normal. Open table in a new tab To verify if re-emergence of measurable infliximab after addition of an immunomodulator was associated with effective biological anti-TNF activity in serum, we performed competition assays in 2 of the patients using sera obtained before and 3 months after the addition of an immunomodulator. The results of these competition assays showed the restoration of effective anti-TNF blockade in serum after introduction of an immunomodulator (Figure 1B).DiscussionLoss of response to infliximab is a common clinical problem, evolving in up to 13% of patients annually over the course of treatment. A paramount cause for loss of response is the formation of anti-infliximab antibodies, which may hasten the drug clearance and/or directly neutralize its biological effects.10Yanai H. Hanauer S.B. Assessing response and loss of response to biological therapies in IBD.Am J Gastroenterol. 2011; 106: 685-698Crossref PubMed Scopus (263) Google Scholar, 11Allez M. Karmiris K. Louis E. et al.Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects.J Crohn's Colitis. 2010; 4: 355-366Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar Concomitant immunomodulator therapy has been shown to reduce the rate of antidrug antibodies,1Baert 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: 601-608Crossref PubMed Scopus (1844) Google Scholar, 7Hanauer S.B. Wagner C.L. Bala M. et al.Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease.Clin Gastroenterol Hepatol. 2004; 2: 542-553Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 8Vermeire S. Noman M. Van Assche G. et al.Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease.Gut. 2007; 56: 1226-1231Crossref PubMed Scopus (507) Google Scholar and also recently was shown to be clinically superior to monotherapy in both clinical trials of infliximab as well as in population cohorts of infliximab- and adalimumab-treated patients.12Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2390) Google Scholar, 13Sokol H. Seksik P. Carrat F. et al.Usefulness of co-treatment with immunomodulators in patients with inflammatory bowel disease treated with scheduled infliximab maintenance therapy.Gut. 2010; 59: 1363-1368Crossref PubMed Scopus (141) Google Scholar, 14van der Valk M.E. van Oijen M.G. Crohn's disease patients treated with adalimumab benefit from co-treatment with immunomodulators.Gut. 2012; 61: 324-325Crossref PubMed Scopus (14) Google Scholar However, given earlier reports that did not show unequivocal superiority of combination therapy with thiopurines or methotrexate as an adjunct to infliximab,15Van Assche G. Magdelaine-Beuzelin C. D'Haens G. et al.Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial.Gastroenterology. 2008; 134: 1861-1868Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 16Feagan B.G. McDonald J. Ponich T. et al.A randomized trial of methotrexate (MTX) in combination with infliximab (IFX) for the treatment of Crohn's disease (CD).Gastroenterology. 2008; 134: 682cGoogle Scholar, 17Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT 1 randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3580) Google Scholar and in light of the possible adverse events associated with the immunomodulators, many patients still are treated by anti-TNF monotherapy. When these patients develop loss of response as a result of absent drug in serum and circulating ATI, there are 2 conceptually possible approaches to maximize the anti-TNF effect: dose-intensification or switching to another anti-TNF. Two retrospective studies reported conflicting results pertaining to the usefulness of dose intensification in the event of formed ATIs,4Afif W. Loftus E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (425) Google Scholar, 5Pariente B. Pineton de Chambrun G. Krzysiek R. et al.Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 1199-1206Crossref PubMed Scopus (97) Google Scholar and most investigators still advocate a switch within class in patients with immunogenic loss of response.10Yanai H. Hanauer S.B. Assessing response and loss of response to biological therapies in IBD.Am J Gastroenterol. 2011; 106: 685-698Crossref PubMed Scopus (263) Google Scholar An alternative to these 2 options could be the addition of an immunomodulator, whether azathioprine/6-mercaptopurine or methotrexate. This is an especially attractive option in patients who already have exhausted other anti-TNFs, making a switch to another anti-TNF unreasonable. However, the efficacy of adding an immunomodulator in the event of already formed ATIs is unknown.Azathioprine induces RAC1-mediated T-cell apoptosis and previously was shown to incrementally delete memory T-cell clones after repeated cognate antigen exposures.18Tiede I. Fritz G. Strand S. et al.CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.J Clin Invest. 2003; 111: 1133-1145Crossref PubMed Scopus (701) Google Scholar, 19Ben-Horin S. Goldstein I. Fudim E. et al.Early preservation of immune effector functions followed by eventual T cell memory depletion: a model for the delayed onset of the effect of thiopurines.Gut. 2009; 58: 396-403Crossref PubMed Scopus (53) Google Scholar The present novel observations reflect these bench-side experiments by showing that the addition of azathioprine (or methotrexate) gradually can eliminate a preformed memory response to infliximab antigen in the event of repeated infliximab exposure. Subsequently, this has lead to a decline of ATI titers in the circulation and to concomitant restoration of effective anti-TNF level and regained clinical response. It is important to note that ATIs occasionally may disappear spontaneously in some patients after continuation of infliximab without alteration. However, ATI positivity in those cases was mostly a one-time event,20Steenholdt C. Al-Khalaf M. Brynskov J. et al.Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 2209-2217Crossref PubMed Scopus (88) Google Scholar unlike the stable ATI positivity over consecutive infusions in our study, which was reversed only upon addition of an immunomodulator. Moreover, transient ATI positivity mostly was unrelated to genuine loss of response. In fact, loss of response in that study was correlated with a persistent increase of ATIs on repeat measurements and not with transient ATIs.20Steenholdt C. Al-Khalaf M. Brynskov J. et al.Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 2209-2217Crossref PubMed Scopus (88) Google Scholar This is reminiscent of our series, in which all patients had clinical loss of response with persistently increased ATIs in serial measurements, which later reverted to a persistently negative status after immunomodulator addition. Thus, we believe these observations are distinct from haphazard fluctuations of ATIs and attest that a persistent ATI+/infliximab- phenotype associated with clinical loss of response can be reversed to a stable ATI-/infliximab+ state by addition of an immunomodulator.The present observations are limited by the small number of patients included, which is at least partly owing to the stringent inclusion criteria we applied, excluding patients without ATI positivity on serial measurements and also excluding patients who were dose-intensified simultaneously with immunomodulator addition. Nonetheless, we believe the results suggesting that immunomodulators may abolish preformed immune reaction to biological drugs could bear significant impact on clinical practice, if corroborated by larger-scale studies. Another cautionary note is that it remains to be established in larger cohorts what percentage of patients with ATI after biological monotherapy will indeed respond favorably to the proposed addition of an immunomodulator at that point in time because the efficacy of immunomodulators varies between different individuals.In conclusion, these preliminary observations suggest that the addition of an immunomodulator to infliximab-treated patients with immunogenic loss of response may eliminate the ATI and restore effective drug levels, thereby leading to regained clinical response. If corroborated by larger, preferably prospective, studies, the addition of an immunomodulator to patients with a loss of response to anti-TNF in the presence of measurable antidrug antibodies may prove to be an important additional tool in our arsenal of therapeutic interventions to optimize the care of IBD patients. Immunogenicity of infliximab and other anti–tumor necrosis factor (TNF) drugs in inflammatory bowel disease (IBD) is an important cause for diminished clinical response, which may culminate in treatment discontinuation.1Baert 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: 601-608Crossref PubMed Scopus (1844) Google Scholar The most commonly practiced salvage therapy is dose-intensification, but the long-term efficacy of this strategy is still questionable.2Katz L. Gisbert J.P. Manoogian B. et al.Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response.Inflamm Bowel Dis. 2012; 18: 2026-2033Crossref PubMed Scopus (112) Google Scholar, 3Regueiro M. Siemanowski B. Kip K.E. et al.Infliximab dose intensification in Crohn's disease.Inflamm Bowel Dis. 2007; 13: 1093-1099Crossref PubMed Scopus (119) Google Scholar Moreover, the ability of dose-intensification to overcome loss of response owing to antidrug antibodies remains controversial.4Afif W. Loftus E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (425) Google Scholar, 5Pariente B. Pineton de Chambrun G. Krzysiek R. et al.Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2012; 18: 1199-1206Crossref PubMed Scopus (97) Google Scholar Switching to another anti-TNF in such patients with immunogenic loss of response has been advocated.4Afif W. Loftus E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (425) Google Scholar, 6Sandborn W.J. Rutgeerts P. Enns R. et al.Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.Ann Intern Med. 2007; 146: 829-838Crossref PubMed Scopus (844) Google Scholar However, the efficacy of switching to anti-TNF is not optimal; it hastens the exhaustion of the limited therapeutic arsenal in IBD, and it may be impractical in some patients who already failed other anti-TNFs. An altogether alternative approach to these 2 strategies could be the addition of an immunomodulator to reverse an established immune sensitization to anti-TNF. Although starting combination immunomodulator and infliximab is known to reduce the rate of development of antibodies to infliximab (ATI),7Hanauer S.B. Wagner C.L. Bala M. et al.Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease.Clin Gastroenterol Hepatol. 2004; 2: 542-553Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 8Vermeire S. Noman M. Van Assche G. et al.Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease.Gut. 2007; 56: 1226-1231Crossref PubMed Scopus (507) Google Scholar it is unknown if the post factum addition of immunomodulators also can reverse established loss of response owing to antidrug antibodies. Therefore, the aim of the present study was to describe a series of patients who developed ATIs and undetectable infliximab, in whom ATIs were eliminated and effective infliximab drug levels were restored after the addition of an immunomodulator as a co-agent with continued infliximab. MethodsPatientsThe charts of all infliximab-treated IBD patients in the period between 2009 and 2011 who had available serial infliximab and anti-infliximab antibody levels were screened for this study. Patients who developed a loss of response to infliximab (ie, secondary nonresponse) in the presence of anti-infliximab antibodies and undetectable trough levels of infliximab were identified. Of these patients, we further identified patients who were treated at this time point by the addition of immunomodulators as a co-treatment with infliximab and recorded their clinical course and serial serum infliximab/ATI results. To reduce potential technical-related pitfalls and confounding effects, we only included patients who had at least 2 consecutive measurements showing no infliximab and positive ATI before initiation of immunomodulators. Furthermore, we only included patients whose only intervention was the addition of an immunomodulator. Thus, we excluded patients who were simultaneously dose-intensified because in these patients the subsequent pharmacokinetic observations may be the result of the anti-TNF dose increase rather than the addition of an immunomodulator. This study was approved by the institutional ethics committees of Sheba and Rambam Medical Centers.DefinitionsMaintenance dosing was defined as at least one 8-week interval of infliximab infusion after the induction course. Loss of response was defined by the re-emergence of IBD symptoms coupled with a decision of the treating physician to alter the therapy, that is, to increase the dose, switch anti-TNF, add an immunomodulator, or refer the patient for Crohn's disease–related surgery.2Katz L. Gisbert J.P. Manoogian B. et al.Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response.Inflamm Bowel Dis. 2012; 18: 2026-2033Crossref PubMed Scopus (112) Google Scholar Response to intervention was defined as improvement of the symptoms as per the treating physician's judgment, coupled with a decision to continue the treatment strategy without alterations.Determining Drug, Antidrug Antibodies, and Anti–TNF Activity of SeraInfliximab and ATI levels in the serum were measured by enzyme-linked immunosorbent assay as previously described.9Ben-Horin S. Yavzori M. Katz L. et al.The immunogenic part of infliximab is the F(ab')2, but measuring antibodies to the intact infliximab molecule is more clinically useful.Gut. 2011; 60: 41-48Crossref PubMed Scopus (180) Google Scholar For assessment of anti-TNF activity, exogenous human recombinant TNF (PeproTech, Rocky Hill, NJ) was added in graded concentrations and was pre-incubated for 60 minutes at room temperature with thawed sera of patients obtained at the time of loss of response and at 3 months after initiation of concomitant immunomodulator. After preincubation, free TNF content in serum was measured by enzyme-linked immunosorbent assay for human TNF (R&D, Minneapolis, MN), as per the manufacturer's instructions, and results were expressed as optical density. PatientsThe charts of all infliximab-treated IBD patients in the period between 2009 and 2011 who had available serial infliximab and anti-infliximab antibody levels were screened for this study. Patients who developed a loss of response to infliximab (ie, secondary nonresponse) in the presence of anti-infliximab antibodies and undetectable trough levels of infliximab were identified. Of these patients, we further identified patients who were treated at this time point by the addition of immunomodulators as a co-treatment with infliximab and recorded their clinical course and serial serum infliximab/ATI results. To reduce potential technical-related pitfalls and confounding effects, we only included patients who had at least 2 consecutive measurements showing no infliximab and positive ATI before initiation of immunomodulators. Furthermore, we only included patients whose only intervention was the addition of an immunomodulator. Thus, we excluded patients who were simultaneously dose-intensified because in these patients the subsequent pharmacokinetic observations may be the result of the anti-TNF dose increase rather than the addition of an immunomodulator. This study was approved by the institutional ethics committees of Sheba and Rambam Medical Centers. The charts of all infliximab-treated IBD patients in the period between 2009 and 2011 who had available serial infliximab and anti-infliximab antibody levels were screened for this study. Patients who developed a loss of response to infliximab (ie, secondary nonresponse) in the presence of anti-infliximab antibodies and undetectable trough levels of infliximab were identified. Of these patients, we further identified patients who were treated at this time point by the addition of immunomodulators as a co-treatment with infliximab and recorded their clinical course and serial serum infliximab/ATI results. To reduce potential technical-related pitfalls and confounding effects, we only included patients who had at least 2 consecutive measurements showing no infliximab and positive ATI before initiation of immunomodulators. Furthermore, we only included patients whose only intervention was the addition of an immunomodulator. Thus, we excluded patients who were simultaneo" @default.
• W2018178851 created "2016-06-24" @default.
• W2018178851 creator A5026843306 @default.
• W2018178851 creator A5035713128 @default.
• W2018178851 creator A5037885531 @default.
• W2018178851 creator A5047907008 @default.
• W2018178851 creator A5048216450 @default.
• W2018178851 creator A5056533442 @default.
• W2018178851 creator A5062860652 @default.
• W2018178851 creator A5080002704 @default.
• W2018178851 creator A5089704358 @default.
• W2018178851 date "2013-04-01" @default.
• W2018178851 modified "2023-10-18" @default.
• W2018178851 title "Addition of an Immunomodulator to Infliximab Therapy Eliminates Antidrug Antibodies in Serum and Restores Clinical Response of Patients With Inflammatory Bowel Disease" @default.
• W2018178851 cites W1964015549 @default.
• W2018178851 cites W1978593886 @default.
• W2018178851 cites W1997999969 @default.
• W2018178851 cites W1998966252 @default.
• W2018178851 cites W2020710276 @default.
• W2018178851 cites W2080037503 @default.
• W2018178851 cites W2081071002 @default.
• W2018178851 cites W2086767087 @default.
• W2018178851 cites W2093504865 @default.
• W2018178851 cites W2102952098 @default.
• W2018178851 cites W2114095680 @default.
• W2018178851 cites W2117212747 @default.
• W2018178851 cites W2118559127 @default.
• W2018178851 cites W2121609590 @default.
• W2018178851 cites W2126807394 @default.
• W2018178851 cites W2134803931 @default.
• W2018178851 cites W2136628679 @default.
• W2018178851 cites W2159143303 @default.
• W2018178851 cites W2171341132 @default.
• W2018178851 doi "https://doi.org/10.1016/j.cgh.2012.10.020" @default.
• W2018178851 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23103905" @default.
• W2018178851 hasPublicationYear "2013" @default.
• W2018178851 type Work @default.
• W2018178851 sameAs 2018178851 @default.
• W2018178851 citedByCount "276" @default.
• W2018178851 countsByYear W20181788512013 @default.
• W2018178851 countsByYear W20181788512014 @default.
• W2018178851 countsByYear W20181788512015 @default.
• W2018178851 countsByYear W20181788512016 @default.
• W2018178851 countsByYear W20181788512017 @default.
• W2018178851 countsByYear W20181788512018 @default.
• W2018178851 countsByYear W20181788512019 @default.
• W2018178851 countsByYear W20181788512020 @default.
• W2018178851 countsByYear W20181788512021 @default.
• W2018178851 countsByYear W20181788512022 @default.
• W2018178851 countsByYear W20181788512023 @default.
• W2018178851 crossrefType "journal-article" @default.
• W2018178851 hasAuthorship W2018178851A5026843306 @default.
• W2018178851 hasAuthorship W2018178851A5035713128 @default.
• W2018178851 hasAuthorship W2018178851A5037885531 @default.
• W2018178851 hasAuthorship W2018178851A5047907008 @default.
• W2018178851 hasAuthorship W2018178851A5048216450 @default.
• W2018178851 hasAuthorship W2018178851A5056533442 @default.
• W2018178851 hasAuthorship W2018178851A5062860652 @default.
• W2018178851 hasAuthorship W2018178851A5080002704 @default.
• W2018178851 hasAuthorship W2018178851A5089704358 @default.
• W2018178851 hasConcept C126322002 @default.
• W2018178851 hasConcept C159654299 @default.
• W2018178851 hasConcept C203014093 @default.
• W2018178851 hasConcept C2777138892 @default.
• W2018178851 hasConcept C2778260677 @default.
• W2018178851 hasConcept C2779134260 @default.
• W2018178851 hasConcept C2779280984 @default.
• W2018178851 hasConcept C2780479503 @default.
• W2018178851 hasConcept C71924100 @default.
• W2018178851 hasConcept C90924648 @default.
• W2018178851 hasConceptScore W2018178851C126322002 @default.
• W2018178851 hasConceptScore W2018178851C159654299 @default.
• W2018178851 hasConceptScore W2018178851C203014093 @default.
• W2018178851 hasConceptScore W2018178851C2777138892 @default.
• W2018178851 hasConceptScore W2018178851C2778260677 @default.
• W2018178851 hasConceptScore W2018178851C2779134260 @default.
• W2018178851 hasConceptScore W2018178851C2779280984 @default.
• W2018178851 hasConceptScore W2018178851C2780479503 @default.
• W2018178851 hasConceptScore W2018178851C71924100 @default.
• W2018178851 hasConceptScore W2018178851C90924648 @default.
• W2018178851 hasIssue "4" @default.
• W2018178851 hasLocation W20181788511 @default.
• W2018178851 hasLocation W20181788512 @default.
• W2018178851 hasOpenAccess W2018178851 @default.
• W2018178851 hasPrimaryLocation W20181788511 @default.
• W2018178851 hasRelatedWork W1998231725 @default.
• W2018178851 hasRelatedWork W2014462309 @default.
• W2018178851 hasRelatedWork W2032015456 @default.
• W2018178851 hasRelatedWork W2070285775 @default.
• W2018178851 hasRelatedWork W2124908533 @default.
• W2018178851 hasRelatedWork W2258300052 @default.
• W2018178851 hasRelatedWork W2408939568 @default.
• W2018178851 hasRelatedWork W2418837291 @default.
• W2018178851 hasRelatedWork W2512626908 @default.
• W2018178851 hasRelatedWork W46359855 @default.
• W2018178851 hasVolume "11" @default.
• W2018178851 isParatext "false" @default.
• W2018178851 isRetracted "false" @default.

• next