ORIGINAL ARTICLE
Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease Casper Steenholdt, MD, PhD,* Madeline T. Frederiksen, MD,* Klaus Bendtzen, MD, DMSc,w Mark A. Ainsworth, MD, PhD, DMSc,* Ole Ø. Thomsen, MD, DMSc,* and Jørn Brynskov, MD, DMSc*
Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n = 8). Disappearance of antiADL Abs during therapy (n = 3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 mg/mL in antiADL Ab-negative samples (P < 0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P < 0.0001), and shorter treatment duration (P < 0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency
Received for publication February 4, 2015; accepted May 25, 2015. From the *Department of Gastroenterology, Herlev Hospital, Herlev; and wInstitute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark. This study has in part been accepted for presentation at the ECCO congresses in 2015. Study design: C.S., K.B.; collection of data: C.S., M.T.F.; analysis and interpretation of data: C.S., M.T.F., K.B., M.A.A., O.Ø.T., J.B.; drafting the manuscript: C.S.; revising the manuscript and approval of final manuscript: C.S., M.T.F., K.B., M.A.A., O.Ø.T., J.B. Within the last 2 years: C.S. has served as speaker for Abbvie, MSD, Pfizer; and advisory board member for Pfizer. K.B. has served as a speaker for Pfizer, Novo-Nordisk, and Biomonitor, and owns stocks in Novo-Nordisk and Biomonitor. O.Ø.T. has served as primary investigator for Amgen, Biogen, Genentech, Hoffmann-La Roche, Novo-Nordisk, and Pfizer. J.B. has served as advisory board member for Abbvie. The remaining authors declare that they have nothing to disclose. Reprints: Casper Steenholdt, MD, PhD, Department of Gastroenterology, Herlev Hospital, Herlev Ringvej 75, Herlev DK-2730, Denmark (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.jcge.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 50, Number 6, July 2016
over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations. Key Words: IBD, TNF, adalimumab, antibodies, antidrug antibodies, transiency, therapeutic drug monitoring
(J Clin Gastroenterol 2016;50:483–489)
A
nti-tumor necrosis factor (TNF)-a therapy is effective in the treatment of patients with moderate to severe active inflammatory bowel disease (IBD) refractory to conventional immunosuppressive agents.1 Adalimumab (ADL), a fully human IgG1-k monoclonal antibody (Ab), is increasingly used both as primary anti-TNF drug and in patients switching from a different TNF-inhibitor due to treatment failure or side effects.2,3 There is, however, considerable variation in response to ADL therapy with notable proportions of patients either needing an intensified ADL regimen to maintain response or having to discontinue ADL therapy due to loss of response.4–6 It is recognized that serum drug levels of the chimeric mouse-human TNF inhibitor, infliximab (IFX), and formation of anti-IFX Abs is associated with efficacy of IFX therapy.7 Moreover, clinical interventions guided by these parameters have been shown to aid cost-effective drug usage in case of treatment failure.8–12 Accumulating data suggest that similar conditions also may apply to ADL therapy despite its “humanized” nature.13–17 Hence, immunologic recognition of ADL can result in production of anti-ADL Abs, which primarily target the TNF-binding sites of ADL and thereby interfere with binding of drug to TNF.18,19 Anti-ADL Abs may also increase drug clearance via formation of immune complexes which are rapidly absorbed from the circulation and degraded.19,20 Accordingly, anti-ADL Abs have been associated with low serum trough levels of ADL and treatment failure.13–16,21 Existing trials have focused mainly on clinical implications of antiADL Ab formation using point-prevalence obtained at diverse timepoints. Little is thus known about temporal characteristics of anti-ADL Ab formation including variations during ongoing ADL therapy. This is relevant because drug levels and anti-drug Abs are subject to change over time. Anti-IFX Abs may even become undetectable during continued IFX maintenance therapy for yet unknown reasons.22–24 The aim of this study was therefore to examine appearance of anti-ADL Abs including course of changes www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
483
J Clin Gastroenterol
Steenholdt et al
during ongoing ADL therapy, and their impact on ADL serum levels and clinical outcomes in patients with IBD. Furthermore, the study aimed to assess methodological explanations for observed variations in anti-ADL Ab detection over time.
METHODS
Volume 50, Number 6, July 2016
patients having tested positive for anti-ADL Abs were reassessed for anti-ADL Abs in all available samples from the department’s biobank collected at later timepoints during continued ADL therapy. Serum was collected after centrifugation of 10 mL venous blood and sent at room temperature for analysis under blinded conditions (Biomonitor A/S, Denmark).
Study Design and Patients This was a retrospective cohort study of IBD patients treated with ADL at a single tertiary IBD center until July, 2014 (Department of Gastroenterology, Herlev Hospital, Denmark). The study population comprised all patients who had been assessed for Abs against ADL. Anti-ADL Ab assessments had been done at the discretion of the treating senior gastroenterologist based on clinical grounds and without any local guidelines to define patients in whom testing should be done. The reasons for anti-ADL Ab testings are detailed below and in Table 1, and were primarily attributable to treatment failure (44%) or sustained remission (46%). The study was approved by the Danish Health and Medical Authority, the Danish Data Protection Agency, and the regional ethics committee.
Evaluations Variables potentially associated with development of anti-ADL Abs were predefined and consisted of patient and disease characteristics, demographics, and characteristics of the anti-TNF treatment regimen. Clinical outcome of ADL treatment was classified according to the treating physician’s global evaluation as noted in the patient files. Primary nonresponse was complete lack of effect of ADL induction and consequently followed by discontinuation of ADL therapy. Secondary ADL treatment failure was defined as initial favorable response to ADL induction and maintenance therapy, and later followed by loss of clinical effect with symptoms of active disease despite dose optimization and finally resulting in discontinuation of ADL. Maintained ADL response was defined as sustained clinical effect of ADL maintenance therapy at time of follow-up or at time of ADL discontinuation.
Serum Analyses Samples All serum analyses had been done at the discretion of the treating physician. Included samples were obtained as trough levels except for a minority collected in relation to side effects or at manifestation of treatment failure. Unless a repeat anti-ADL Ab assessment had already been done,
ADL and Anti-ADL Abs Serum concentrations of ADL and anti-ADL Abs were measured by clinically validated fluid-phase radioimmunoassays (RIAs) as previously detailed (limit of ADL detection was 0.60 mg/mL; positive anti-ADL Abs when >2 activity in pooled normal human serum).16 Of note, RIA for anti-drug Abs is less drug-sensitive than other currently available assays and detects Abs in the presence of moderate amounts of drug.25 In those cases where antiADL Abs became undetectable again (ie, potential transiency) then (A) the positive anti-ADL Abs samples were reassessed in independent analyses by RIA and now quantified as titers (cpm relative to a pool of normal human serum); (B) the negative anti-ADL Ab samples were assessed by a solid phase enzyme immunoassay (EIA) not prone to drug interference26; and (C) all anti-ADL Ab positive and negative samples were assessed for both antiADL Abs and ADL by a cell-based reporter gene assay (RGA), which measures the functional activity of drug and antidrug Abs at the cellular TNF receptor level.26–28
Statistics Descriptive statistics were given as percentages for discrete variables, and as medians with interquartile ranges (IQR) for continuous variables. Univariate analysis of discrete variables was done by Fisher exact test or w2 test, and in cases with lack of patients in one subgroup, an estimated odds ratio was calculated by adding 0.5 to each value. Univariate analysis of continuous variables was done by Mann-Whitney test (unpaired) or Wilcoxon signed-rank test (paired). Kaplan-Meier curves were used to assess temporal formation and evolution of anti-ADL Abs and survival curves were compared by log-rank test. In case of serial available anti-ADL Ab measurements, time to first positive anti-ADL Ab detection, or to last negative antiADL Ab detection, respectively, was used. Statistical analyses were done in SPSS, version 22 (IBM, Somer, NY) and GraphPad Prism, version 5 (GraphPad Software, San Diego, CA). Two-sided P-values of 4 weeks. zThiopurines or methotrexate in standard doses. 5-ASA indicates 5-aminosalicylic acid; Abs, antibodies; ADL, adalimumab; IFX, infliximab; IQR, interquartile range.
of reassessment (Fig. 1 and Supplementary Table, Supplemental Digital Content 1, http://links.lww.com/JCG/ A183). Importantly, this patient experienced secondary treatment failure on ADL indicating that these Abs were functionally active. Therefore, lack of anti-ADL Ab detection at repeat assessments across time can also be
caused by false-negative anti-ADL Ab measurements both by some binding (RIA) and functional assays (RGA) likely due to assay interference with drug present in the sample.
Correlations Between Anti-ADL Abs and ADL Concentrations in Serum Samples ADL was undetectable in anti-ADL Ab positive samples, whereas all samples except one without detection of anti-ADL Abs contained ADL (median, 7.4 mg/mL; IQR = 4.6-11.4; P < 0.0001) (Fig. 3).
Anti-ADL Abs and Clinical Outcomes Clinical outcomes of ADL therapy in patients stratified according to anti-ADL Ab status is detailed in Table 1. Clinical classification was supported by biochemical parameters shown in Figure 4. Anti-ADL Abs significantly associated with secondary ADL treatment failure (odds ratio estimated 67, P < 0.0001), and with ADL discontinuation irrespectively of underlying reason, for example, primary nonresponse, secondary treatment failure, or side effects (odds ratio estimated 57, P < 0.0001). Time on ADL maintenance therapy without treatment failure was significantly (P < 0.0001) shorter among patients with anti-ADL Ab formation as compared with those without (Fig. 5). FIGURE 2. Time to detection of anti-ADL Abs. Development of anti-ADL Abs over time during ongoing ADL maintenance therapy. Vertical bars are censored cases. Ab indicates antibody; ADL, adalimumab.
DISCUSSION Anti-TNF therapy with IFX may induce production of anti-IFX Abs via immunologic recognition of the murine
486 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 50, Number 6, July 2016
Characteristics of Antibodies Against Adalimumab
FIGURE 3. ADL concentrations according to anti-ADL Ab status. ADL concentrations in serum samples positive (+) for anti-ADL Abs (n = 17) or negative () for anti-ADL Abs (n = 77) by radioimmunoassay (ADL not assessed n = 39). Horizontal lines denote medians and interquartile ranges. *P < 0.0001. Ab indicates antibody; ADL, adalimumab.
component of the drug molecule, and lead to low serum IFX levels, insufficient treatment effect, manifest treatment failure, or hypersensitivity reactions.29–31 As anti-IFX Abs are highly drug specific, it is suggested to switch from IFX to another TNF inhibitor such as ADL in case of anti-IFX Ab detection.7,16 This strategy has been supported by observations in clinical trials.8–12 Until recently, ADL was considered to be less immunogenic than IFX due to its molecular structure consisting of human sequences only. However, accumulating data, including observations presented here, show that ADL therapy results in a comparable frequency of anti-drug Ab formation in up to 30% of patients.3,13–16,21,32 Of note, and still analogous to conditions for anti-IFX Abs, our data in line with others show that anti-ADL Abs are associated with elimination of drug in the circulation and therapeutic failure.13,14,16,21 Other important observations in this study are that anti-ADL Abs usually appear in the circulation within the first year of ADL therapy and with decreasing frequency of formation over time. Comparable findings have been reported for anti-IFX Abs indicating that it is a common characteristic of Abs against TNF inhibitors to generally appear in the blood within approximately 1 year after initiation of therapy.24,33 This observation may to some extent explain differences in reported frequencies of anti-ADL Ab formation due to diverse timepoints of assessments.13–15,21 As was also shown here, variable reportings on the frequency of anti-ADL Ab development may, however, also be caused by methodological differences between Copyright
r
FIGURE 4. Biochemical markers of disease activity. Biochemical markers of disease activity in patients with loss of response (n = 26), and maintained response (n = 33) to ADL therapy at time of ADL initiation and at time of follow-up (or at ADL discontinuation), respectively. *P < 0.01; **P < 0.001. ADL indicates adalimumab
applied assays.26,28,34 Taken together, the risk of anti-ADL Ab development is very low if 1 year of ADL therapy has elapsed without formation of anti-ADL Abs. We also explored the temporal evolution of anti-ADL Abs during continued ADL maintenance therapy. In a majority of 8 patients, detected anti-ADL Abs persisted at repeat assessments by RIA. As anti-ADL Abs were associated with elimination of drug in the systemic circulation and symptoms of treatment failure, we suggest ADL cessation to be considered if anti-ADL Abs are detected in
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
487
Steenholdt et al
FIGURE 5. ADL treatment duration. Duration of ADL maintenance therapy without ADL treatment failure in patients positive (+) or negative () for anti-ADL Abs. *P < 0.0001. Ab indicates antibody; ADL, adalimumab.
combination with low or undetectable drug. Of note, however, previously detected anti-ADL Abs became undetectable during continued ADL therapy in a minority of 3 patients by RIA. This has not been described in patients with IBD previously, but extend recent anecdotal observations in rheumatoid arthritis.35 A similar phenomenon has been reported for anti-IFX Abs.22 Hence, antiIFX Abs with no apparent clinical relevance become undetectable in 26% to 42% of detections during continued IFX therapy due to unknown reasons.22–24 We hypothesized that fluctuation in anti-ADL Ab detection is explained by methodological characteristics of different analytical techniques used for this purpose. Therefore, we next assessed anti-ADL Abs in those 3 patients where anti-ADL Abs became undetectable during continued ADL therapy both by an EIA less prone to drug interference than the fluid-phase RIA otherwise used, as well as by a functional RGA.26–28 Interestingly, all samples were negative for antiADL Abs and had detectable ADL by RGA.36 Congruent with this, anti-ADL Abs were undetectable also by EIA at later reassessment in 2 of the 3 patients. In support of nonfunctionality of anti-ADL Abs detected by RIA in these 2 patients, both had maintained clinical response on ADL at time of follow-up. This shows, that disappearance of anti-ADL Abs across time can be caused by detection in (some) binding assays of nonfunctional anti-ADL Abs, which later become undetectable; that is, nonfunctional nonpersistent anti-ADL Abs (false-positive detections). The mechanism(s) could be lowered anti-ADL Ab production due to drug-induced immunologic high-zone tolerance; alternatively, that immune complexes consisting of antiADL Abs bound to ADL are cleared from the system and therefore not detected. In contrast, one of the 3 patients where anti-ADL Abs disappeared during continued ADL therapy as determined by RIA and RGA, in fact had persistent anti-ADL Abs by EIA. As this patient experienced secondary ADL treatment failure, lack of anti-ADL Ab detection was likely caused by false-negative anti-ADL Ab measurements at time of reassessment by RIA and RGA, for example, due to the presence of drug in the serum.37 Taken together, to accommodate for methodological biases, anti-ADL Ab test results should always be interpreted in a clinical context and taking clinical treatment responses into account. Furthermore, in case of combined detection of ADL and anti-ADL Abs, or
J Clin Gastroenterol
Volume 50, Number 6, July 2016
disappearance of anti-ADL Abs, we recommend repeated assessments at later timepoints by principally different and less drug-sensitive assays. Study limitations include a small sample size and consequences of a retrospective study design. For example, this was not a formal evaluation of the kinetics of anti-ADL Abs, as timing of sampling was without standardized timepoints of assessments. Furthermore, evaluations of anti-ADL Abs were done at the discretion of the physician and the study population may not have been representative for all ADL treated patients. However, the distribution of clinical response types in this cohort as detailed in Table 1 appears representative for patients in anti-TNF therapy indicating this selection bias is unlikely. Clinical outcomes of ADL therapy was classified according to the treating physician’s global evaluation and supported by biochemical parameters. Even though disease activity scoring systems and endoscopic disease activity assessments are preferred, the clinician’s global evaluation reflects the clinical setting and is commonly used in retrospective studies.13,29 Part of this study population had been used in a previous study which reported on associations between serum ADL trough levels and anti-ADL Abs and clinical outcomes as detailed in the reference.16 However, the current population included a larger number of patients due to longer recruitment period, had longer follow-up time, and included repeat analyses on individual patients. In conclusion, anti-ADL Abs develop in about one fourth of IBD patients and usually appear in the circulation within the first year of therapy. As anti-ADL Abs generally persist during continued ADL therapy and associate with elimination of drug and treatment failure, cessation of ADL therapy should be considered once anti-ADL Abs have been detected. However, methodological biases may result in false-positive and false-negative anti-ADL Ab detections, and interpretation of test results should therefore take clinical treatment outcomes into account.
REFERENCES 1. D’Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011;106:199–212. 2. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65. 3. Sandborn WJ, Van AG, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–265. 4. 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: 674–684. 5. Chaparro M, Panes J, Garcia V, et al. Long-term durability of response to adalimumab in Crohn’s disease. Inflamm Bowel Dis. 2012;18:685–690. 6. Baert F, Glorieus E, Reenaers C, et al. Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn’s patients. J Crohns Colitis. 2013;7:154–160. 7. Khanna R, Sattin BD, Afif W, et al. Review article: a clinician’s guide for therapeutic drug monitoring of infliximab
488 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19. 20. 21.
22.
Volume 50, Number 6, July 2016
in inflammatory bowel disease. Aliment Pharmacol Ther. 2013; 38:447–459. 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;105:1133–1139. Velayos FS, Kahn JG, Sandborn WJ, et al. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11:654–666. Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63: 919–927. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, et al. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20:1996–2003. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522–530. West RL, Zelinkova Z, Wolbink GJ, et al. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28:1122–1126. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137:1628–1640. Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharmacol Ther. 2014;40:620–628. Frederiksen MT, Ainsworth MA, Brynskov J, et al. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis. 2014;20:1714–1721. Roblin X, Rinaudo M, Del TE, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109: 1250–1256. van Schouwenburg PA, van de Stadt LA, de Jong RN, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72:104–109. Bendtzen K. Anti-TNF-alpha biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy. 2012; 4:1167–1179. Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–88. Paul S, Moreau AC, Del TE, et al. Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20: 1288–1295. Steenholdt C, Al-Khalaf M, Brynskov J, et al. Clinical implications of variations in anti-infliximab antibody levels in
Copyright
r
Characteristics of Antibodies Against Adalimumab
23. 24. 25.
26.
27.
28.
29.
30.
31.
32.
33. 34.
35.
36. 37.
2015 Wolters Kluwer Health, Inc. All rights reserved.
patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2209–2217. 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;108:962–971. Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63:1258–1264. Svenson M, Geborek P, Saxne T, et al. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology. 2007;46:1828–1834. Steenholdt C, Ainsworth MA, Tovey M, et al. Comparison of techniques for monitoring infliximab and antibodies against infliximab in Crohn’s disease. Ther Drug Monit. 2013;35: 530–538. Lallemand C, Kavrochorianou N, Steenholdt C, et al. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFalpha antagonists. J Immunol Methods. 2011;373:229–239. Steenholdt C, Bendtzen K, Brynskov J, et al. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn’s disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. 2014;109:1055–1064. Ben-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; 60:41–48. 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 metaanalysis. Am J Gastroenterol. 2013;108:40–47. Steenholdt C, Svenson M, Bendtzen K, et al. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34:51–58. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–333. 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;348:601–608. Steenholdt C, Bendtzen K, Brynskov J, et al. Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn’s disease. J Crohns Colitis. 2015;9:238–245. 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;305:1460–1468. Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factoralpha antagonists. Discov Med. 2013;15:201–211. Van Schouwenburg PA, Krieckaert CL, Rispens T, et al. Longterm measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Ann Rheum Dis. 2013;72:1680–1686.
www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
489
Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease Casper Steenholdt, MD, PhD,* Madeline T. Frederiksen, MD,* Klaus Bendtzen, MD, DMSc,w Mark A. Ainsworth, MD, PhD, DMSc,* Ole Ø. Thomsen, MD, DMSc,* and Jørn Brynskov, MD, DMSc*
Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n = 8). Disappearance of antiADL Abs during therapy (n = 3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 mg/mL in antiADL Ab-negative samples (P < 0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P < 0.0001), and shorter treatment duration (P < 0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency
Received for publication February 4, 2015; accepted May 25, 2015. From the *Department of Gastroenterology, Herlev Hospital, Herlev; and wInstitute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark. This study has in part been accepted for presentation at the ECCO congresses in 2015. Study design: C.S., K.B.; collection of data: C.S., M.T.F.; analysis and interpretation of data: C.S., M.T.F., K.B., M.A.A., O.Ø.T., J.B.; drafting the manuscript: C.S.; revising the manuscript and approval of final manuscript: C.S., M.T.F., K.B., M.A.A., O.Ø.T., J.B. Within the last 2 years: C.S. has served as speaker for Abbvie, MSD, Pfizer; and advisory board member for Pfizer. K.B. has served as a speaker for Pfizer, Novo-Nordisk, and Biomonitor, and owns stocks in Novo-Nordisk and Biomonitor. O.Ø.T. has served as primary investigator for Amgen, Biogen, Genentech, Hoffmann-La Roche, Novo-Nordisk, and Pfizer. J.B. has served as advisory board member for Abbvie. The remaining authors declare that they have nothing to disclose. Reprints: Casper Steenholdt, MD, PhD, Department of Gastroenterology, Herlev Hospital, Herlev Ringvej 75, Herlev DK-2730, Denmark (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.jcge.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 50, Number 6, July 2016
over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations. Key Words: IBD, TNF, adalimumab, antibodies, antidrug antibodies, transiency, therapeutic drug monitoring
(J Clin Gastroenterol 2016;50:483–489)
A
nti-tumor necrosis factor (TNF)-a therapy is effective in the treatment of patients with moderate to severe active inflammatory bowel disease (IBD) refractory to conventional immunosuppressive agents.1 Adalimumab (ADL), a fully human IgG1-k monoclonal antibody (Ab), is increasingly used both as primary anti-TNF drug and in patients switching from a different TNF-inhibitor due to treatment failure or side effects.2,3 There is, however, considerable variation in response to ADL therapy with notable proportions of patients either needing an intensified ADL regimen to maintain response or having to discontinue ADL therapy due to loss of response.4–6 It is recognized that serum drug levels of the chimeric mouse-human TNF inhibitor, infliximab (IFX), and formation of anti-IFX Abs is associated with efficacy of IFX therapy.7 Moreover, clinical interventions guided by these parameters have been shown to aid cost-effective drug usage in case of treatment failure.8–12 Accumulating data suggest that similar conditions also may apply to ADL therapy despite its “humanized” nature.13–17 Hence, immunologic recognition of ADL can result in production of anti-ADL Abs, which primarily target the TNF-binding sites of ADL and thereby interfere with binding of drug to TNF.18,19 Anti-ADL Abs may also increase drug clearance via formation of immune complexes which are rapidly absorbed from the circulation and degraded.19,20 Accordingly, anti-ADL Abs have been associated with low serum trough levels of ADL and treatment failure.13–16,21 Existing trials have focused mainly on clinical implications of antiADL Ab formation using point-prevalence obtained at diverse timepoints. Little is thus known about temporal characteristics of anti-ADL Ab formation including variations during ongoing ADL therapy. This is relevant because drug levels and anti-drug Abs are subject to change over time. Anti-IFX Abs may even become undetectable during continued IFX maintenance therapy for yet unknown reasons.22–24 The aim of this study was therefore to examine appearance of anti-ADL Abs including course of changes www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
483
J Clin Gastroenterol
Steenholdt et al
during ongoing ADL therapy, and their impact on ADL serum levels and clinical outcomes in patients with IBD. Furthermore, the study aimed to assess methodological explanations for observed variations in anti-ADL Ab detection over time.
METHODS
Volume 50, Number 6, July 2016
patients having tested positive for anti-ADL Abs were reassessed for anti-ADL Abs in all available samples from the department’s biobank collected at later timepoints during continued ADL therapy. Serum was collected after centrifugation of 10 mL venous blood and sent at room temperature for analysis under blinded conditions (Biomonitor A/S, Denmark).
Study Design and Patients This was a retrospective cohort study of IBD patients treated with ADL at a single tertiary IBD center until July, 2014 (Department of Gastroenterology, Herlev Hospital, Denmark). The study population comprised all patients who had been assessed for Abs against ADL. Anti-ADL Ab assessments had been done at the discretion of the treating senior gastroenterologist based on clinical grounds and without any local guidelines to define patients in whom testing should be done. The reasons for anti-ADL Ab testings are detailed below and in Table 1, and were primarily attributable to treatment failure (44%) or sustained remission (46%). The study was approved by the Danish Health and Medical Authority, the Danish Data Protection Agency, and the regional ethics committee.
Evaluations Variables potentially associated with development of anti-ADL Abs were predefined and consisted of patient and disease characteristics, demographics, and characteristics of the anti-TNF treatment regimen. Clinical outcome of ADL treatment was classified according to the treating physician’s global evaluation as noted in the patient files. Primary nonresponse was complete lack of effect of ADL induction and consequently followed by discontinuation of ADL therapy. Secondary ADL treatment failure was defined as initial favorable response to ADL induction and maintenance therapy, and later followed by loss of clinical effect with symptoms of active disease despite dose optimization and finally resulting in discontinuation of ADL. Maintained ADL response was defined as sustained clinical effect of ADL maintenance therapy at time of follow-up or at time of ADL discontinuation.
Serum Analyses Samples All serum analyses had been done at the discretion of the treating physician. Included samples were obtained as trough levels except for a minority collected in relation to side effects or at manifestation of treatment failure. Unless a repeat anti-ADL Ab assessment had already been done,
ADL and Anti-ADL Abs Serum concentrations of ADL and anti-ADL Abs were measured by clinically validated fluid-phase radioimmunoassays (RIAs) as previously detailed (limit of ADL detection was 0.60 mg/mL; positive anti-ADL Abs when >2 activity in pooled normal human serum).16 Of note, RIA for anti-drug Abs is less drug-sensitive than other currently available assays and detects Abs in the presence of moderate amounts of drug.25 In those cases where antiADL Abs became undetectable again (ie, potential transiency) then (A) the positive anti-ADL Abs samples were reassessed in independent analyses by RIA and now quantified as titers (cpm relative to a pool of normal human serum); (B) the negative anti-ADL Ab samples were assessed by a solid phase enzyme immunoassay (EIA) not prone to drug interference26; and (C) all anti-ADL Ab positive and negative samples were assessed for both antiADL Abs and ADL by a cell-based reporter gene assay (RGA), which measures the functional activity of drug and antidrug Abs at the cellular TNF receptor level.26–28
Statistics Descriptive statistics were given as percentages for discrete variables, and as medians with interquartile ranges (IQR) for continuous variables. Univariate analysis of discrete variables was done by Fisher exact test or w2 test, and in cases with lack of patients in one subgroup, an estimated odds ratio was calculated by adding 0.5 to each value. Univariate analysis of continuous variables was done by Mann-Whitney test (unpaired) or Wilcoxon signed-rank test (paired). Kaplan-Meier curves were used to assess temporal formation and evolution of anti-ADL Abs and survival curves were compared by log-rank test. In case of serial available anti-ADL Ab measurements, time to first positive anti-ADL Ab detection, or to last negative antiADL Ab detection, respectively, was used. Statistical analyses were done in SPSS, version 22 (IBM, Somer, NY) and GraphPad Prism, version 5 (GraphPad Software, San Diego, CA). Two-sided P-values of 4 weeks. zThiopurines or methotrexate in standard doses. 5-ASA indicates 5-aminosalicylic acid; Abs, antibodies; ADL, adalimumab; IFX, infliximab; IQR, interquartile range.
of reassessment (Fig. 1 and Supplementary Table, Supplemental Digital Content 1, http://links.lww.com/JCG/ A183). Importantly, this patient experienced secondary treatment failure on ADL indicating that these Abs were functionally active. Therefore, lack of anti-ADL Ab detection at repeat assessments across time can also be
caused by false-negative anti-ADL Ab measurements both by some binding (RIA) and functional assays (RGA) likely due to assay interference with drug present in the sample.
Correlations Between Anti-ADL Abs and ADL Concentrations in Serum Samples ADL was undetectable in anti-ADL Ab positive samples, whereas all samples except one without detection of anti-ADL Abs contained ADL (median, 7.4 mg/mL; IQR = 4.6-11.4; P < 0.0001) (Fig. 3).
Anti-ADL Abs and Clinical Outcomes Clinical outcomes of ADL therapy in patients stratified according to anti-ADL Ab status is detailed in Table 1. Clinical classification was supported by biochemical parameters shown in Figure 4. Anti-ADL Abs significantly associated with secondary ADL treatment failure (odds ratio estimated 67, P < 0.0001), and with ADL discontinuation irrespectively of underlying reason, for example, primary nonresponse, secondary treatment failure, or side effects (odds ratio estimated 57, P < 0.0001). Time on ADL maintenance therapy without treatment failure was significantly (P < 0.0001) shorter among patients with anti-ADL Ab formation as compared with those without (Fig. 5). FIGURE 2. Time to detection of anti-ADL Abs. Development of anti-ADL Abs over time during ongoing ADL maintenance therapy. Vertical bars are censored cases. Ab indicates antibody; ADL, adalimumab.
DISCUSSION Anti-TNF therapy with IFX may induce production of anti-IFX Abs via immunologic recognition of the murine
486 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 50, Number 6, July 2016
Characteristics of Antibodies Against Adalimumab
FIGURE 3. ADL concentrations according to anti-ADL Ab status. ADL concentrations in serum samples positive (+) for anti-ADL Abs (n = 17) or negative () for anti-ADL Abs (n = 77) by radioimmunoassay (ADL not assessed n = 39). Horizontal lines denote medians and interquartile ranges. *P < 0.0001. Ab indicates antibody; ADL, adalimumab.
component of the drug molecule, and lead to low serum IFX levels, insufficient treatment effect, manifest treatment failure, or hypersensitivity reactions.29–31 As anti-IFX Abs are highly drug specific, it is suggested to switch from IFX to another TNF inhibitor such as ADL in case of anti-IFX Ab detection.7,16 This strategy has been supported by observations in clinical trials.8–12 Until recently, ADL was considered to be less immunogenic than IFX due to its molecular structure consisting of human sequences only. However, accumulating data, including observations presented here, show that ADL therapy results in a comparable frequency of anti-drug Ab formation in up to 30% of patients.3,13–16,21,32 Of note, and still analogous to conditions for anti-IFX Abs, our data in line with others show that anti-ADL Abs are associated with elimination of drug in the circulation and therapeutic failure.13,14,16,21 Other important observations in this study are that anti-ADL Abs usually appear in the circulation within the first year of ADL therapy and with decreasing frequency of formation over time. Comparable findings have been reported for anti-IFX Abs indicating that it is a common characteristic of Abs against TNF inhibitors to generally appear in the blood within approximately 1 year after initiation of therapy.24,33 This observation may to some extent explain differences in reported frequencies of anti-ADL Ab formation due to diverse timepoints of assessments.13–15,21 As was also shown here, variable reportings on the frequency of anti-ADL Ab development may, however, also be caused by methodological differences between Copyright
r
FIGURE 4. Biochemical markers of disease activity. Biochemical markers of disease activity in patients with loss of response (n = 26), and maintained response (n = 33) to ADL therapy at time of ADL initiation and at time of follow-up (or at ADL discontinuation), respectively. *P < 0.01; **P < 0.001. ADL indicates adalimumab
applied assays.26,28,34 Taken together, the risk of anti-ADL Ab development is very low if 1 year of ADL therapy has elapsed without formation of anti-ADL Abs. We also explored the temporal evolution of anti-ADL Abs during continued ADL maintenance therapy. In a majority of 8 patients, detected anti-ADL Abs persisted at repeat assessments by RIA. As anti-ADL Abs were associated with elimination of drug in the systemic circulation and symptoms of treatment failure, we suggest ADL cessation to be considered if anti-ADL Abs are detected in
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
487
Steenholdt et al
FIGURE 5. ADL treatment duration. Duration of ADL maintenance therapy without ADL treatment failure in patients positive (+) or negative () for anti-ADL Abs. *P < 0.0001. Ab indicates antibody; ADL, adalimumab.
combination with low or undetectable drug. Of note, however, previously detected anti-ADL Abs became undetectable during continued ADL therapy in a minority of 3 patients by RIA. This has not been described in patients with IBD previously, but extend recent anecdotal observations in rheumatoid arthritis.35 A similar phenomenon has been reported for anti-IFX Abs.22 Hence, antiIFX Abs with no apparent clinical relevance become undetectable in 26% to 42% of detections during continued IFX therapy due to unknown reasons.22–24 We hypothesized that fluctuation in anti-ADL Ab detection is explained by methodological characteristics of different analytical techniques used for this purpose. Therefore, we next assessed anti-ADL Abs in those 3 patients where anti-ADL Abs became undetectable during continued ADL therapy both by an EIA less prone to drug interference than the fluid-phase RIA otherwise used, as well as by a functional RGA.26–28 Interestingly, all samples were negative for antiADL Abs and had detectable ADL by RGA.36 Congruent with this, anti-ADL Abs were undetectable also by EIA at later reassessment in 2 of the 3 patients. In support of nonfunctionality of anti-ADL Abs detected by RIA in these 2 patients, both had maintained clinical response on ADL at time of follow-up. This shows, that disappearance of anti-ADL Abs across time can be caused by detection in (some) binding assays of nonfunctional anti-ADL Abs, which later become undetectable; that is, nonfunctional nonpersistent anti-ADL Abs (false-positive detections). The mechanism(s) could be lowered anti-ADL Ab production due to drug-induced immunologic high-zone tolerance; alternatively, that immune complexes consisting of antiADL Abs bound to ADL are cleared from the system and therefore not detected. In contrast, one of the 3 patients where anti-ADL Abs disappeared during continued ADL therapy as determined by RIA and RGA, in fact had persistent anti-ADL Abs by EIA. As this patient experienced secondary ADL treatment failure, lack of anti-ADL Ab detection was likely caused by false-negative anti-ADL Ab measurements at time of reassessment by RIA and RGA, for example, due to the presence of drug in the serum.37 Taken together, to accommodate for methodological biases, anti-ADL Ab test results should always be interpreted in a clinical context and taking clinical treatment responses into account. Furthermore, in case of combined detection of ADL and anti-ADL Abs, or
J Clin Gastroenterol
Volume 50, Number 6, July 2016
disappearance of anti-ADL Abs, we recommend repeated assessments at later timepoints by principally different and less drug-sensitive assays. Study limitations include a small sample size and consequences of a retrospective study design. For example, this was not a formal evaluation of the kinetics of anti-ADL Abs, as timing of sampling was without standardized timepoints of assessments. Furthermore, evaluations of anti-ADL Abs were done at the discretion of the physician and the study population may not have been representative for all ADL treated patients. However, the distribution of clinical response types in this cohort as detailed in Table 1 appears representative for patients in anti-TNF therapy indicating this selection bias is unlikely. Clinical outcomes of ADL therapy was classified according to the treating physician’s global evaluation and supported by biochemical parameters. Even though disease activity scoring systems and endoscopic disease activity assessments are preferred, the clinician’s global evaluation reflects the clinical setting and is commonly used in retrospective studies.13,29 Part of this study population had been used in a previous study which reported on associations between serum ADL trough levels and anti-ADL Abs and clinical outcomes as detailed in the reference.16 However, the current population included a larger number of patients due to longer recruitment period, had longer follow-up time, and included repeat analyses on individual patients. In conclusion, anti-ADL Abs develop in about one fourth of IBD patients and usually appear in the circulation within the first year of therapy. As anti-ADL Abs generally persist during continued ADL therapy and associate with elimination of drug and treatment failure, cessation of ADL therapy should be considered once anti-ADL Abs have been detected. However, methodological biases may result in false-positive and false-negative anti-ADL Ab detections, and interpretation of test results should therefore take clinical treatment outcomes into account.
REFERENCES 1. D’Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011;106:199–212. 2. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65. 3. Sandborn WJ, Van AG, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257–265. 4. 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: 674–684. 5. Chaparro M, Panes J, Garcia V, et al. Long-term durability of response to adalimumab in Crohn’s disease. Inflamm Bowel Dis. 2012;18:685–690. 6. Baert F, Glorieus E, Reenaers C, et al. Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn’s patients. J Crohns Colitis. 2013;7:154–160. 7. Khanna R, Sattin BD, Afif W, et al. Review article: a clinician’s guide for therapeutic drug monitoring of infliximab
488 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19. 20. 21.
22.
Volume 50, Number 6, July 2016
in inflammatory bowel disease. Aliment Pharmacol Ther. 2013; 38:447–459. 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;105:1133–1139. Velayos FS, Kahn JG, Sandborn WJ, et al. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11:654–666. Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63: 919–927. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, et al. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20:1996–2003. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522–530. West RL, Zelinkova Z, Wolbink GJ, et al. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28:1122–1126. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137:1628–1640. Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharmacol Ther. 2014;40:620–628. Frederiksen MT, Ainsworth MA, Brynskov J, et al. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis. 2014;20:1714–1721. Roblin X, Rinaudo M, Del TE, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109: 1250–1256. van Schouwenburg PA, van de Stadt LA, de Jong RN, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72:104–109. Bendtzen K. Anti-TNF-alpha biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy. 2012; 4:1167–1179. Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–88. Paul S, Moreau AC, Del TE, et al. Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20: 1288–1295. Steenholdt C, Al-Khalaf M, Brynskov J, et al. Clinical implications of variations in anti-infliximab antibody levels in
Copyright
r
Characteristics of Antibodies Against Adalimumab
23. 24. 25.
26.
27.
28.
29.
30.
31.
32.
33. 34.
35.
36. 37.
2015 Wolters Kluwer Health, Inc. All rights reserved.
patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2209–2217. 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;108:962–971. Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63:1258–1264. Svenson M, Geborek P, Saxne T, et al. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology. 2007;46:1828–1834. Steenholdt C, Ainsworth MA, Tovey M, et al. Comparison of techniques for monitoring infliximab and antibodies against infliximab in Crohn’s disease. Ther Drug Monit. 2013;35: 530–538. Lallemand C, Kavrochorianou N, Steenholdt C, et al. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFalpha antagonists. J Immunol Methods. 2011;373:229–239. Steenholdt C, Bendtzen K, Brynskov J, et al. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn’s disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. 2014;109:1055–1064. Ben-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; 60:41–48. 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 metaanalysis. Am J Gastroenterol. 2013;108:40–47. Steenholdt C, Svenson M, Bendtzen K, et al. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34:51–58. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–333. 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;348:601–608. Steenholdt C, Bendtzen K, Brynskov J, et al. Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn’s disease. J Crohns Colitis. 2015;9:238–245. 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;305:1460–1468. Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factoralpha antagonists. Discov Med. 2013;15:201–211. Van Schouwenburg PA, Krieckaert CL, Rispens T, et al. Longterm measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Ann Rheum Dis. 2013;72:1680–1686.
www.jcge.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
489
