Antibodies To Infliximab Formation Research Articles

Does HLA-DQA1*05 carriage have a greater impact on the outcome of infliximab therapy for isolated small-bowel Crohn's disease?

Carriage of HLA-DQA1*05 is thought to increase the formation of anti-tumour necrosis factor alpha (TNF-α) antibodies, reducing the drug efficacy in Crohn's disease (CD) patients. However, little data are currently available for small-bowel Crohn's disease (SB-CD). A specific assessment of the impact of HLA-DQA1*05 on the clinical response to treatment with infliximab (IFX), a TNF-α antagonists, in SB-CD patients is necessary. We conducted a single-center retrospective study that included 106 SB-CD patients treated with IFX. The serum samples were collected for antibodies to infliximab (ATI) testing and HLA-DQA1*05 genotyping. Double-balloon enteroscopy (DBE) was performed following the IFX treatment, with endoscopic outcomes evaluated using the partial simple endoscopic score for CD (pSES-CD), whereas the clinical response was assessed with the Crohn's disease activity index (CDAI). Multivariate logistic regression and multivariate COX regression analyses were employed to analyze the correlation of the HLA-DQA1*05 genotypes with other clinical variables. In this study, 30.2% of SB-CD patients carried the HLA-DQA1*05 allele, which significantly increased their risk of ATI generation (odds ratio [OR]=2.337, p=.043), but it was not associated with the clinical response to IFX and drug persistence (OR=2.356, p=.145; OR=0.457, p=.249). The endoscopic remission rates were 40.6% (13/32) and 55.4% (41/74) in HLA-DQA1*05 carriers and non-carriers, respectively. HLA-DQA1*05 was not associated with endoscopic remission (OR=0.684, p=.414). The HLA-DQA1*05 variant is identified as a significant risk factor of ATI formation in Chinese patients with SB-CD, but is not associated with the clinical response of IFX treatment and endoscopic remission of SB lesions.

Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease.

Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50μg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48μg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95μg/mL, p = .03). The HLA-DQA1*05 rs2097432GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

Intermittent Appearance of Antibodies to Infliximab Is Not Associated With Reduced Efficacy in Patients With Inflammatory Bowel Diseases.

To assess the clinical significance of antibodies to infliximab (ATI) formation in patients with inflammatory bowel disease (IBD). Infliximab therapy in patients with IBD is highly effective though up to 50% of patients lose response to infliximab. ATI formation occurs in 6% to 60% of patients on scheduled infliximab maintenance therapy. Infliximab trough levels and ATI at trough were prospectively determined in patients with IBD on maintenance infliximab therapy. Patients on infliximab maintenance therapy with at least 3 ATI measurements were included. Patients were divided into 2 groups: sustained negative (<1 µg/mL) ATI levels, and fluctuating ATI levels (at least 1 sample with ATI <1 and at least one >1 µg/mL). Forty-eight patients with IBD with available clinical data and serum samples were included. 25 patients had sustained low ATI levels and 23 patients had fluctuating ATI levels. Both groups were similar in IBD subtype distribution (Crohn's disease in 73.9% and 60%), mean serum albumin levels (4.2 vs. 3.9 g/dL), and mean trough serum infliximab levels (3.3 vs. 4.6 µg/mL) in fluctuating ATI and low ATI groups, respectively. There were no significant differences in the rate of clinical response (64% vs. 76%) and mean serum C-reactive protein levels (9.4 vs. 8.5 mg/dL, ULN=5) in the fluctuating ATI and low ATI groups. Similar rates of clinical response in the fluctuating ATI and low ATI groups were observed in ulcerative colitis (33% vs. 40%) and Crohn's disease (76% vs. 100%). The fluctuating pattern of appearance of ATI in patients with IBD was not associated with loss of clinical response or a rise in C-reactive protein. The authors suggest that in clinical decision making, only sustained appearance of ATI should be considered as an adverse therapeutic factor.

P026 Investigating Predictors of Antibodies to Infliximab Formation in Inflammatory Bowel Disease – The Importance of Immunomodulators

BACKGROUND: Anti-tumor necrosis factor (TNF)-α have revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Loss of response to anti-TNFs is a clinical challenge and has been associated with formation of antibodies. AIM: To identify predictive factors of antibodies to infliximab (ATI) formation in IBD patients. METHODS: Retrospective single-center study including all consecutive IBD patients being treated with infliximab with at least one ATI and infliximab level determination and with a minimum follow-up of six months after the first testing. Presence of ATI was considered if at least one determination was positive during the follow-up and infliximab levels at this testing were registered. Clinical and demographic data obtained included disease phenotype, surgical background, duration of infliximab therapy, use of premedication, concomitant immunomodulator therapy at the time of testing, compliance, occurrence of an infusion reaction and biochemical assessment at the time of first induction treatment. RESULTS: 104 patients were included, 56 females (53.8%) with mean age of 38.2 ± 13.1 years. The overall prevalence of detectable ATI was 28.8% (30) and the mean time to its formation was 32.8 ± 24.3 months. Most (66.7%) patients with ATI had simultaneously nontherapeutic levels of infliximab. Patients treated with concomitant immunomodulators were less likely to develop ATI (33% versus 88%, P < 0.001). Additionally, it was found that patients with Ulcerative Colitis (UC) were more likely to have detectable ATI than those with Crohn Disease (CD) (44.4% vs 23.4%, P = 0.04). However, UC patients were less treated with concomitant immunomodulators (48.1% vs 80.5%, P = 0.001). At logistic regression analysis only lack of immunomodulator use (P < 0.001; OR 13.5, CI 95%, 4.63–40.0) was independently associated with ATI formation. CONCLUSION(S): Concomitant immunomodulator therapy was the only protective factor for the ATI formation, supporting its institution to prevent loss of response to anti-TNFs.

P103 Impact of premedication and other variables on the formation of antibodies to infliximab in pediatric inflammatory bowel disease

BACKGROUND: Infliximab is a chimeric monoclonal antibody against tumor necrosis factor α approved for induction and maintenance of remission in inflammatory bowel disease (IBD). Loss of response to infliximab is a clinical challenge and has been associated with drug immunogenicity and formation of antibodies to infliximab (ATI). The role of premedication with corticosteroids in preventing ATI formation is controversial and poorly studied in children. The aim of this cross sectional study is to investigate the effect of corticosteroid premedication on the prevalence of ATI, as well as to identify other variables that may affect ATI formation and infliximab level. METHODS: The study cohort included pediatric IBD patients treated with infliximab at our institution and had first ATI testing between 1/1/2003 and 6/30/2018. Clinical data obtained included routine premedication, duration of infliximab therapy, infliximab level, age, sex, BMI percentile, albumin, CRP, fecal calprotectin, occurrence of an infusion reaction (IR), and concomitant use of immunomodulator at the time of testing. The above variables were compared between the premedicated and non-premedicated groups, ATI positive and negative groups, and detectable and undetectable infliximab level groups and analyzed with descriptive statistics. Continuous variables were assessed by t-test and categorical variables by chi-square contingency analysis. P value &lt;0.05 indicates statistical significance. This study was approved by the Institutional Review Board. RESULTS: We identified a total of 289 patients, 171 males and 118 females with mean age of 14.6 ± 3.2 years. Reasons for ATI testing were therapeutic drug monitoring (59%), flare (33%), abnormal labs (7%), or IR (1%). The overall prevalence of detectable ATI was 35% (101/289). When we compared the premedicated group (n = 213) to the nonpremedicated group (n = 76), we found no significant difference in ATI prevalence (38% vs 28%, P = 0.113). The premedicated group had significantly longer infliximab therapy duration prior to the first ATI testing (491 ± 605 vs 161 ± 247 days, P &lt; 0.001), and higher BMI percentile (60.5 ± 29.8 vs 48.3 ± 30.6, P = 0.002). No significant differences were found in other variables. Next, we observed that patients with detectable ATI were on infliximab therapy longer (550 ± 634 days vs 321 ± 487 days, P ≤ 0.001) and were less likely to be treated with concomitant immunomodulators (11% vs 23%, P = 0.011) compared to the undetectable ATI group. None of the other variables were significantly different. In addition, we found that detectable infliximab correlated significantly with normal CRP and albumin (P = 0.004 and P ≤ 0.001). Patients with undetectable infliximab were more likely to have an IR (10.4%) than patients with detectable infliximab (1.3%) (P &lt; 0.001). Interestingly, concomitant immunomodulator use did not influence the likelihood of having detectable infliximab (19% vs 19%, P = 0.983). CONCLUSION(S): Our data suggests that premedication does not appear to decrease the prevalence of ATI formation. Our study confirms that concomitant immunomodulator therapy does lead to less ATI formation; however, immunomodulator therapy did not correlate with detectable infliximab. Detectable infliximab was the only variable that correlated with improved clinical parameters (CRP and albumin). Having undetectable infliximab, but not the lack of premedication or presence of ATI, increased the likelihood of IR.

The Impact of Combination Therapy on Infliximab Levels and Antibodies in Children and Young Adults With Inflammatory Bowel Disease.

The aim of this study was to evaluate the effect of combination therapy with methotrexate or 6-mercaptopurine on infliximab levels (IFXL) and antibodies to infliximab (ATI). Infliximab (IFX) is a highly effective therapy for inflammatory bowel disease (IBD). Unfortunately, 25%-50% of patients will lose response to IFX. Loss of response is correlated with low IFXL and ATI formation which accelerates drug clearance. Combination therapy is thought to decrease ATI formation. We performed a cross-sectional analysis of 223 pediatric and young adult patients with IBD on IFX. IFXL and ATI were measured and compared between subjects on current combination therapy, prior combination therapy, and IFX monotherapy. Eighty-four (37.7%) patients were on combination therapy and 139 (62.3%) were on IFX monotherapy. Within the current monotherapy group, 112 (80.6%) had previously been on combination therapy, while 27 (19.4%) had never been on a concomitant immunomodulator. Patients currently on combination therapy had a higher IFXL (17.00 ± 1.33 μg/mL) than those currently on IFX monotherapy (13.18 ± 1.26 μg/mL), P < 0.01. IFXL was lowest in patients who had never been on combination therapy (11.53 ± 2.05 μg/mL) and highest in patients currently on combination therapy (17.00 ± 1.33 μg/mL). Patients currently on combination therapy had a lower rate of detectable ATI (9.5%) compared with those on monotherapy (20.0%) in multivariate analysis (odds ratio [OR]: 0.3; 95% confidence interval (CI), 0.1-0.7, P < 0.01). Current or prior combination therapy is associated with higher IFXL and lower rates of ATI formation.

Less Anti-infliximab Antibody Formation in Paediatric Crohn Patients on Concomitant Immunomodulators.

To evaluate the effect of immunomodulators on formation of antibodies to infliximab (ATI) in paediatric patients with Crohn disease (CD) and the association of ATI and loss of response. Retrospective multicentre observational study (January 2009-December 2014) among Dutch children with CD treated with infliximab (IFX). ATI formation was analysed with Chi-square test and time-to-ATI formation with Kaplan-Meier and log-rank test. A total of 229 children were identified. ATIs were measured in 162 patients (70.7%) and 25 (15%) developed ATIs: 6 of 62 (10%) on continuous combined immunosuppression (CCI), 11 of 81 (14%) on early combined immunosuppression (ECI), and 8 of 19 (42%) on IFX monotherapy. ATI formation was higher in patients on IFX monotherapy compared to CCI (P = 0.003) and ECI (P = 0.008), whereas no significant difference was found between CCI and ECI. Sixteen out of 25 patients (64%) with ATIs had loss of response, compared with 32 of 137 patients (19%) without ATIs (P < 0.00002, log rank 0.02). Among patients treated with ECI, 10 of 55 (18%) developed ATIs within the first 12 months, compared to 1 of 26 (4%) after more than 12 months. In children with CD combination therapy is associated with significant reduction of antibody formation and prolonged effectivity compared to IFX monotherapy. ECI for at least 12 months, followed by IFX monotherapy, may be an equally effective alternative to CCI.

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

ObjectiveAlthough low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate...

Antibody Response to Infliximab and its Impact on Pharmacokinetics can be Transient

Infliximab (IFX) is successfully used in the treatment of inflammatory bowel diseases but some patients generate antibodies to IFX (ATI) jeopardizing the pharmacokinetics of the drug. Little is known about the factors influencing ATI formation and whether or not this immune reaction is permanent. Our aim was to investigate the kinetics of ATI formation and drug levels in relation to inflammatory markers and the clinical evolution of the patients. IFX trough and ATI levels were measured retrospectively in 1,232 consecutive serum samples of 90 (64 Crohn's disease and 26 ulcerative colitis) patients, 57 with previously detected and 33 without antibodies with a new homogenous mobility shift assay. Testing with new assay confirmed ATI in 53/90 patients (59%) and 37/90 patients (41%) were ATI negative. In 15/53 patients (28%), ATI disappeared over time whereas in 38/53 patients (72%) ATI persisted. The 26/38 (68%) patients with sustained ATI needed to discontinue IFX treatment compared with 2/15 (13%) patients with transient ATI (relative risk 5.1; 95% confidence interval 1.4-19.0; P=0.0005). An IFX trough level at week 14<2.2 μg/ml predicted IFX discontinuation due to persistent loss of response (LOR) or hypersensitivity reactions with 74% specificity and 82% sensitivity (likelihood ratio 3.1; P=0.0026). ATI may be transient and do not always lead to a worse clinical outcome. Sustained high levels of ATI, however, lead to permanent LOR. Patients with low IFX trough levels at week 14 are at risk for ATI formation and IFX discontinuation. Therefore, we recommend to measure IFX trough levels at week 14 and at time of LOR. When undetectable or low, ATI should be determined and if positive followed up on consecutive time points to rule out sustained ATI.

Influence of immunogenicity on the efficacy of longterm treatment of spondyloarthritis with infliximab

BackgroundInfliximab (IFX) is a monoclonal antibody against tumour necrosis factor α that is effective for treating spondyloarthritis (SpA). However, after initial success of the drug some patients lose responsiveness or...

Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: A randomized controlled trial

Background & Aims: We assessed the relationship between antibodies to infliximab (ATI) and the loss of response postinfliximab, infusion reactions and, in a randomized trial, investigated whether intravenous hydrocortisone premedication can reduce ATI. Methods: Initially, we prospectively evaluated clinical response, adverse events, and ATI levels in 53 consecutive patients with Crohn's disease who received 199 infliximab (5 mg/kg) infusions. Subsequently, 80 patients with Crohn's disease were randomized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions. The primary endpoint was reduction in median ATI levels at week 16. Analysis was by intention to treat. Results: Nineteen of our initial 53 patients (36%) developed ATI, including all 7 patients with serious infusion reactions (median ATI level, 19.6 μg/mL). Eleven of 15 patients (73%) who lost their initial response were ATI positive compared with none of 21 continuous responders, (8.9 vs. 0.7 μg/mL, P < 0.0001). Administering a second infusion within 8 weeks of the first (OR, 0.13; 95% CI, 0.03-0.5; P = 0.0007) or concurrent immunosuppressants (OR, 0.19; 95% CI, 0.04-1.03; P = 0.007) significantly reduced ATI formation. In the placebo-controlled trial, ATI levels were lower at week 16 among hydrocortisone-treated patients (1.6 vs. 3.4 μg/mL, P = 0.02), and 26% of hydrocortisone-treated patients developed ATI compared with 42% of placebo-treated patients, P = 0.06. Conclusions: Loss of initial response and infusion reactions post-infliximab is strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduce ATI formation. Intravenous hydrocortisone premedication significantly reduces ATI levels but does not eliminate ATI formation or infusion reactions.