Patients With Low Drug Levels or Antibodies to a Prior Anti–Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti–Tumor Necrosis Factor
Authors: Niels Vande Casteele, Maria T. Abreu, Sarah Flier, Konstantinos Papamichael, Florian Rieder, Mark S. Silverberg, Reena Khanna, Lauren Okada, Lei Yang, Anjali Jain, Adam S. Cheifetz
Journal: Clinical Gastroenterology and Hepatology (2021)

Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases.1Feuerstein J.D. Nguyen G.C. Kupfer S.S. et al.American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease.Gastroenterology. 2017; 153: 827-834Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of development of antibodies against infliximab (IFX) and adalimumab (ADM) 2-fold, regardless of concomitant immunomodulator use.2Sazonovs A. Kennedy N.A. Moutsianas L. et al.HLA-DQA1∗05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's disease.Gastroenterology. 2020; 158: 189-199Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar,3Wilson A. Peel C. Wang Q. et al.HLADQA1∗05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease.Aliment Pharmacol Ther. 2020; 51: 356-363Crossref PubMed Scopus (26) Google Scholar However, there is currently limited evidence showing whether patients who develop antibodies to 1 anti–tumor necrosis factor (TNF) are prone to develop antibodies to the subsequent anti-TNF. Our aim was to investigate the risk of subsequent antibody development in cases (with ADAb to prior anti-TNF) versus control subjects (without ADAb to prior anti-TNF) using a large cohort of patients with inflammatory bowel diseases who underwent TDM with a drug-tolerant assay. Methods are described in the Supplementary Methods. Our study included 5828 subjects of whom 3616/5828 (62.0%) were first treated with IFX and then ADM and 2212/5828 (38.0%) were first treated with ADM and then IFX (Supplementary Table 1). Survival analysis showed that in patients who switched from IFX to ADM, ADAb to IFX was significantly associated with subsequent ADAb formation to ADM (P < .0001) (Figure 1A), with 28.5% of cases who developed ADAb to ADM versus 12.4% of control subjects (hazard ratio, 2.82; 95% confidence interval, 2.35–3.38; P < .0001) (Figure 1B). Increasing concentrations of ADAb to IFX were associated with higher proportions of patients developing ADAb to ADM (P < .0001). ADAb concentrations ≥10 U/mL were associated with a higher proportion of patients developing ADAb to ADM after switch versus those who had ADAb to IFX concentrations <10 U/mL (31.2% vs 21.5%, respectively; P < .0001). In patients who switched from ADM to IFX, survival analysis showed that ADAb to ADM was significantly associated with subsequent ADAb formation to IFX (P < .0001) (Figure 1C), with 39.1% of cases who developed ADAb to IFX versus 15.8% of control subjects (hazard ratio, 3.43; 95% confidence interval, 2.81–4.20; P < .0001) (Figure 1D). In contrast to patients switching from IFX to ADM, increasing concentrations of ADAb to ADM did not result in a significantly higher proportion of patients developing ADAb to IFX. Before switch from IFX to ADM, median (interquartile range) IFX serum concentrations were lower in cases versus control subjects (1.0 μg/mL [1.0–1.0] vs 11.7 μg/mL [4.2–27.1]; P < .0001). Interestingly, even within the control group, lower IFX concentrations were associated with subsequent ADAb formation to ADM (P < .01). Before switch from ADM to IFX, median (interquartile range) ADM serum concentrations were lower in cases versus control subjects (1.6 μg/mL [1.6–3.0] vs 9.2 μg/mL [5.7–13.9]; P < .0001). Similarly, even within the control group, lower ADM concentrations were associated with subsequent ADAb formation to IFX (P < .01). Survival analysis showed that an IFX concentration ≤5 μg/mL was significantly associated with subsequent ADAb formation to ADM (P < .0001), whereas an ADM concentration ≤7.5 μg/mL was significantly associated with subsequent ADAb formation to IFX (P < .0001). In this large retrospective case-control study including several thousand patients with inflammatory bowel diseases treated with anti-TNF, the risk for ADAb to ADM was 2-fold higher when patients had prior antibodies to IFX and the risk for ADAb to IFX was 3-fold higher when patients had prior antibodies to ADM. One hypothesis is that subjects who developed antibodies to the prior and subsequent anti-TNF have a genetic predisposition for developing ADAb.2Sazonovs A. Kennedy N.A. Moutsianas L. et al.HLA-DQA1∗05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's disease.Gastroenterology. 2020; 158: 189-199Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Alternatively, because we found that subtherapeutic drug concentrations to the prior anti-TNF are associated with antibody formation to the subsequent anti-TNF, even in control subjects, one cannot rule out that these subjects suffer from accelerated drug clearance because of common mechanisms that influence anti-TNF pharmacokinetics, which may lead to low drug concentrations and subsequent immunogenicity.4Vande 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: 962-971Crossref PubMed Scopus (289) Google Scholar,5Lefevre P.L.C. Shackelton L.M. Vande Casteele N. Factors influencing drug disposition of monoclonal antibodies in inflammatory bowel disease: implications for personalized medicine.BioDrugs. 2019; 33: 453-468Crossref PubMed Scopus (7) Google Scholar A randomized controlled trial in patients switching anti-TNFs because of antibodies demonstrated that start of the second anti-TNF in combination with an immunomodulator leads to lower rates of clinical failure and more favorable pharmacokinetics, compared with monotherapy.6Roblin X. Williet N. Boschetti G. et al.Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.Gut. 2020; 69: 1206-1212Crossref PubMed Scopus (58) Google Scholar Alternatively, a strategy with optimized monotherapy using proactive TDM may be effective as well, but remains to be assessed in a prospective manner.7Lega S. Phan B.L. Rosenthal C.J. et al.Proactively optimized infliximab monotherapy is as effective as combination therapy in IBD.Inflamm Bowel Dis. 2019; 25: 134-141Crossref PubMed Scopus (47) Google Scholar,8Drobne D. Kurent T. Golob S. et al.Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease.Aliment Pharmacol Ther. 2019; 49: 880-889Crossref PubMed Scopus (23) Google Scholar Our retrospective study has limitations because the lack of clinical data did not allow us to study confounding factors that may affect the factors influencing antibody formation and the lack of patient-relevant clinical outcomes limits its generalizability. In conclusion, we observed a higher likelihood of developing antibodies to a subsequent anti-TNF in patients who developed antibodies to, or had subtherapeutic drug concentrations of the prior anti-TNF. Starting combination therapy and/or conducting proactive TDM should be considered in patients positive for antibodies when switching to another anti-TNF. Retrospective case-control study in 5828 patients with IBD who were selected from a cohort of samples submitted for analysis to a commercial clinical laboratory (Prometheus Biosciences, San Diego, CA). Patients with IBD (Crohn's disease and ulcerative colitis) were selected based on International Classification of Diseases-9 and -10 codes (555.x, 556.x K50.x, K51.x). Subjects needed to have consecutively orders of 2 anti-TNF therapies (infliximab prior to adalimumab or vice versa). Patients were categorized as cases or control subjects according to their antibody status to the prior anti-TNF. Cases were defined as patients where the last available sample before therapy switch was positive for ADAb. Control subjects were defined as patients where all available samples, including the last available sample before therapy switch, were negative for ADAb. For the subsequent anti-TNF, the first available antibody-positive sample was selected that was at least 14 days apart from the selected prior anti-TNF sample. If none of the samples were antibody positive, then the last available sample was selected from the subsequent anti-TNF. Supplementary Table 1 shows the time difference between samples selected for the prior anti-TNF versus subsequent anti-TNF based on the previously mentioned criteria. Serum drug and ADAb concentrations were measured with a drug-tolerant homogenous mobility shift assay (Prometheus Biosciences), as previously published.11 Drug concentrations below lower limit of quantification (LLOQ) or above upper limit of quantification (ULOQ) were replaced with LLOQ or ULOQ (IFX <1.0 μg/mL; ADM <1.6 μg/mL) or ULOQ (IFX >34 μg/mL; ADM >50 μg/mL), respectively. ADAb concentrations <LLOQ (IFX <3.1 U/mL; ADM <1.7 U/mL) were treated as "0," whereas ADAb values >ULOQ (IFX >100 U/mL; ADM >55 U/mL) were treated as ULOQ+1. Descriptive statistics were used with presentation of mean and standard deviation for normally distributed continuous data and median with interquartile rage for nonnormally distributed continuous data. Categorical data were presented as proportions (percent). Patient characteristics were compared between groups using Fisher exact test for categorical variables or Wilcoxon rank sum test for continuous variables. Rate of antibody formation to the subsequent anti-TNF was evaluated in cases and control subjects using chi-square test to compare proportions, Wilcoxon rank sum test to compare continuous variables, and Kaplan-Meier analysis to compare survival. An α level of 5% was considered as threshold for significance. All data analysis was carried out using R version 3.6.2. Deidentified information was extracted from the clinical laboratory database. Clinical information that did not include the Health Insurance Portability and Accountability Act (HIPAA) identifiers was used for analyses. All authors had access to study data, and reviewed and approved the final manuscript. Supplementary Table 1Patient DemographicsCasesControl subjectsAllP valueaBased on Mann-Whitney test for continuous variables and Fisher exact test for categorical variables. (cases vs control subjects)Characteristics of patients who switched from infliximab to adalimumabbContinuous variables are reported as median (IQR), categorical variables are reported as n (%). (n = 3616) Total patients, n (%)2171 (60)1445 (40)3616 Pediatrics (based on prior anti-TNF), n (%)814 (37)481 (32)1295 (36).0098 Males, n (%)975 (45)691 (48)1666 (46).089 CD patients, n (%)1528 (70)1050 (73)2578 (71)c23 subjects (infliximab to adalimumab) and 9 subjects (adalimumab to infliximab) had overlapping International Classification of Diseases codes (CD/UC) and were excluded from these counts..174 UC patients, n (%)627 (29)388 (27)1015 (28)c23 subjects (infliximab to adalimumab) and 9 subjects (adalimumab to infliximab) had overlapping International Classification of Diseases codes (CD/UC) and were excluded from these counts. Age at prior anti-TNF, median (IQR), y25.0 (16.0–44.0)27.0 (17.0–44.0)26.0 (16.0–44.0).016 Time difference (subsequent anti-TNF – prior anti-TNF), median (IQR), wk64.8 (27.9–133.5)105.8 (52.2–173.8)81.1 (35.0–152.0)< .0001Characteristics of patients who switched from adalimumab to infliximabbContinuous variables are reported as median (IQR), categorical variables are reported as n (%). (n = 2212) Total patients, n (%)803 (36)1409 (64)2212 Pediatrics (based on prior anti-TNF), n (%)73 (9)187 (13)260 (12).003 Males, n (%)337 (42)679 (48)1016 (46).005 CD patients, n (%)557 (69)968 (69)1525 (69)c23 subjects (infliximab to adalimumab) and 9 subjects (adalimumab to infliximab) had overlapping International Classification of Diseases codes (CD/UC) and were excluded from these counts..774 UC patients, n (%)243 (30)435 (31)678 (31)c23 subjects (infliximab to adalimumab) and 9 subjects (adalimumab to infliximab) had overlapping International Classification of Diseases codes (CD/UC) and were excluded from these counts. Age at prior anti-TNF, median (IQR), y38.0 (27.0–52.0)33.0 (23.0–48.0)35.0 (24.0–50.0)< .0001 Time difference (subsequent anti-TNF – prior anti-TNF), median (IQR), wk54.5 (30.6–101.0)77.0 (41.0–133.0)68.0 (36.1–122.6)< .0001CD, Crohn's disease; IQR, interquartile range; TNF, tumor necrosis factor; UC, ulcerative colitis.a Based on Mann-Whitney test for continuous variables and Fisher exact test for categorical variables.b Continuous variables are reported as median (IQR), categorical variables are reported as n (%).c 23 subjects (infliximab to adalimumab) and 9 subjects (adalimumab to infliximab) had overlapping International Classification of Diseases codes (CD/UC) and were excluded from these counts. Open table in a new tab CD, Crohn's disease; IQR, interquartile range; TNF, tumor necrosis factor; UC, ulcerative colitis.