Response In Inflammatory Bowel Disease Patients Research Articles

P916 Off-label dose escalation of Ustekinumab in Inflammatory Bowel Disease patients. Incidence rate, timing, dosing patterns and outcomes

Abstract Background In patients with inflammatory bowel disease (IBD), after intravenous induction,Ustekinumab (UST) is administered as maintenance 90 mg every 8 (Q8) or 12 weeks (Q12) subcutaneously. As with other biological drugs, dose intensification may be effective after inadequate response or loss of response. However, different dosing regimens have been used and the best strategy is unknown. Our aim was to evaluate the incidence and efficacy of UST off-label dose escalation in IBD. Methods We performed an observational cohort study in 2 hospitals in Vigo,Spain. All patients who started UST between 1 June 2017 and 31 December 2022 to control their active IBD were enrolled. The primary endpoints were incidence rate and outcomes of UST off-label dose intensification. Secondary endpoints were the timing of dose escalation and the patterns indicated. Results 1 173 IBD patients received UST: females 53.8% (93), mean age 49.7(15.5) years, Crohn´s disease 82% (142), previous anti-TNF 93.6% (162) and vedolizumab 22.5% (39) (Table 1). Subcutaneous UST was maintained Q8 in 63.6% (110) and Q12 in 34.7% (60). Baseline activity data were higher in Q8 patients (p=0.001). At 16 week 23 patients (13.3%) had no response, but 9 (39.1%) became late responders at 6 months. Of the 173 IBD patients included, 38.2% and 30.6 % achieved clinical response and clinical remission at 1 year. Dose escalation was performed in 32.4% (56) with different patterns: 54.5% Q4 (30), 21.8% reinduction plus Q4 (12), 12.7% Q6 (7) and 10.9% only intravenous reinduction (6). The timing of dose escalation was: before 6 months in 19.6% (11), at 12 months 42.8% (24) and at 2 years 73.2% (41). Response and remission were achieved in 28.6% (16) and 41.1% (23) after dose escalation respectively. In 6.4% of the patients (11) a second dose escalation was indicated. Neither previous anti-TNF or vedolizumab nor concomitant use of steroids at starting UST were associated to dose escalation. IBD patients that were initially scheduled to receive subcutaneous UST Q12 needed less dosing escalation (p<0.001). Conclusion Off-label UST dose escalation was frequent and effective in achieving response in IBD patients. The schemes of dose-escalation were heterogeneous between the participants. Patients initially scheduled Q12 due to lower inflammatory activity required less dose escalation.

A booster dose of SARS-COV-2 vaccine improves suboptimal seroconversion rates in patients with inflammatory bowel disease. Results of a prospective multicenter study of GETECCU (VACOVEII study)

BackgroundThe response to SARS-CoV-2 vaccination decreases in inflammatory bowel disease (IBD) patients, specially under anti-TNF treatment. However, data on medium-term effectiveness are limited, specially using new recommended seroconversion rate (>260BAU/mL). Our aim was to evaluate the 6-month>260 BAU-seroconversion rate after full vaccination and after booster-dose. MethodsVACOVEII is a Spanish multicenter, prospective study promoted by GETECCU. IBD patients full vaccinated against SARS-CoV-2 and without previous COVID-19 infection, treated or not with immunosuppressants, were included. The booster dose was administered 6 months after the full vaccination. Seroconversion was set at 260BAU/mL, according to most recent recommendations and was assessed 6 months after the full vaccination and 6 months after booster-dose. ResultsBetween October 2021 and March 2022, 313 patients were included (124 no treatment or mesalazine; 55 immunomodulators; 87 anti-TNF; 19 anti-integrin; and 28 ustekinumab). Most patients received mRNA-vaccines (86%). Six months after full vaccination, overall seroconversion rate was 44.1%, being significantly lower among patients on anti-TNF (19.5%, p<0.001) and ustekinumab (35.7%, p=0.031). The seroconversion rate after booster was 92%. Again, anti-TNF patients had a significantly lower seroconversion rate (67%, p<0.001). mRNA-vaccine improved seroconversion rate (OR 11.720 [95% CI 2.26–60.512]). ConclusionThe full vaccination regimen achieves suboptimal response in IBD patients, specially among those anti-TNF or ustekinumab. The booster dose improves seroconversion rate in all patients, although it remains limited in those treated with anti-TNF. These results reinforce the need to prioritize future booster doses in patients on immunosuppressants therapy, specially under anti-TNF, and using mRNA-vaccines.

Identification of Specific Biomarkers and Pathways in the Treatment Response of Infliximab for Inflammatory Bowel Disease: In-Silico Analysis.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. In biological therapy, infliximab became the first anti-tumor necrosis factor (TNF) agent approved for IBD. Despite this success, infliximab is expensive, often ineffective, and associated with adverse events. Prediction of infliximab resistance would improve overall potential outcomes. Therefore, there is a pressing need to widen the scope of investigating the role of genetics in IBD to their association with therapy response. In the current study, an in-silico analysis of publicly available IBD patient transcriptomics datasets from Gene Expression Omnibus (GEO) are used to identify subsets of differentially expressed genes (DEGs) involved in the pathogenesis of IBD and may serve as potential biomarkers for Infliximab response. Five datasets were found that met the inclusion criteria. The DEGs for datasets were identified using limma R packages through the GEOR2 tool. The probes' annotated genes in each dataset intersected with DGEs from all other datasets. Enriched gene Ontology Clustering for the identified genes was performed using Metascape to explore the possible connections or interactions between the genes. 174 DEGs between IBD and healthy controls were found from analyzing two datasets (GSE14580 and GSE73661), indicating a possible role in the pathogenesis of IBD. Of the 174 DEGs, five genes (SELE, TREM1, AQP9, FPR2, and HCAR3) were shared between all five datasets. Moreover, these five genes were identified as downregulated in the infliximab responder group compared to the non-responder group. We hypothesize that alteration in the expression of these genes leads to an impaired response to infliximab in IBD patients. Thus, these genes can serve as potential biomarkers for the early detection of compromised infliximab response in IBD patients.

Serological response to vaccination against coronavirus disease-19 in patients with inflammatory bowel disease.

Vaccination against coronavirus disease-19 (COVID-19) is effective in preventing the occurrence or reduction in the severity of the infection. Patients with inflammatory bowel disease (IBD) are on immunomodulators, which may alter serological response to vaccination against COVID-19. Accordingly, we studied (i) the serological response to vaccination against COVID-19 in IBD patients and (ii) a comparison of serological response in IBD patients with that in healthy controls. A prospective study was undertaken during a 6-month period (July 2021 to January 2022). Seroconversion was assessed among vaccinated, unvaccinated IBD patients and vaccinated healthy controls using anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G (anti-SARS-CoV-2 IgG) antibody detection enzyme-linked immunosorbent assay (ELISA) kit, and optical density (OD) was measured at 450nm. OD is directly proportional to the antibody concentration. One hundred andthirty-two blood samples were collected from 97 IBD patients (85 [87.6%] ulcerative colitis and 12 [12.4%] Crohn's disease). Forty-one of the seventy-one (57.7%) unvaccinated and 60/61 (98.4%) vaccinated IBD patients tested positive (OD > 0.3) for SARS-CoV-2 IgG antibodies. Fourteen of the sixteen (87.5%) healthy controls tested positive for SARS-CoV-2 IgG antibodies. Vaccinated IBD patients had higher ODs than unvaccinated IBD patients (1.31 [1.09-1.70] vs. 0.53 [0.19-1.32], p < 0.001) and 16 vaccinated healthy controls (1.31 [1.09-1.70] vs. 0.64 [0.43-0.78], p < 0.001). Three of the seventy-one (4.2%) unvaccinated IBD patients reported having recovered from COVID-19. Most IBD patients seroconvert after vaccination against SARS-CoV-2, similar to a healthy population. A large proportion of IBD patients had anti-SARS-CoV-2 antibodies even before vaccination, suggesting the occurrence of herd immunity.

Prognostic Role of Post-Induction Fecal Calprotectin Levels in Patients with Inflammatory Bowel Disease Treated with Biological Therapies.

Background: There is currently scarce knowledge about markers of early therapeutic response in patients with inflammatory bowel disease (IBD) treated with biologics. The aim of this study was to evaluate the role of fecal calprotectin (FC) as an early predictor of mucosal healing and clinical remission. Methods: Data from a multicenter series of 172 IBD patients treated with biologics between 2017 and 2020 were analyzed. Treatment outcomes were mucosal healing and clinical remission assessed at 2 years. FC levels were assessed at 14 weeks (post-induction), at 6 months, and yearly. The receiver operating characteristic (ROC) curve analysis was performed to calculate the best cut-off in % change of FC levels between post-induction and baseline predicting treatment outcomes. Sensitivity, specificity, and accuracy for several post-induction FC cut-off points were also calculated. Results: At 2 years, mucosal healing was noted in 77 patients (44.7%), of whom were 41 Crohn’s disease (CD) and 36 ulcerative colitis (UC) patients, whereas 106 patients experienced clinical remission (61.6%), of whom were 59 CD and 47 UC patients. Both baseline and post-induction FC levels were significantly higher in non-responders as compared to responders. On the other hand, FC decrease was less pronounced in non-responders. Similar results were observed in all subgroups, namely according to disease (CD vs. UC), or treatment used (TNF-inhibitors vs. vedolizumab). The best cut-off points were −86% in % change in FC levels to predict mucosal healing and −83% for clinical remission. Conclusions: The current study suggests a predictive role of post-induction FC assessment to predict treatment response in IBD patients treated with biologics.

P092 Humoral and T cell responses to COVID-19 vaccination in IBD

BackgroundThe characteristics of SARS-CoV-2 vaccine-induced immunity in inflammatory bowel disease (IBD) patients on immune modifying agents has not been clearly defined due to their exclusion in vaccine trials. Emerging results suggest infliximab impairs antibody response compared to vedolizumab. However there has not been direct comparison to controls. We evaluated this with both humoral and T cell response in IBD patients.MethodsAntibody and T cell response were analysed in IBD patients who received BNT162b2 (Pfizer–BioNTech) or ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccination from a single Australian centre. The control group were healthcare workers (HCW) without IBD. Blood samples were taken at 4 time points: at baseline V0 (before vaccination); V1 (7–14 days after vaccine 1); V2 (7–14 days after vaccine 2); V3 (21–42 days after vaccine 2). Antibodies to the S1/2 IgG subunit and receptor-binding protein (RBD) were measured and reported here.Results88 (28 ulcerative colitis, 50 Crohn’s disease) IBD patients were included and compared to 53 healthy controls (Table 1). IBD patients medications included 6 5ASA (6.8%), 6 immunomodulator monotherapy (6.8%), 14 anti-TNF monotherapy (15.9%), 32 anti-TNF combination therapy with immunomodulator (36%), 16 IL12/23 (18%) and 13 vedolizumab (14%). Pre-vaccine baseline sera showed absence of anti-RBD antibodies in all participants. 84 patients (87%) received BNT162b2 and 4 (4.5%) received ChAdOx1 nCoV-19 vaccines. Geometric mean [SD] anti-S1/2 antibody concentrations at 4 weeks after second vaccination (V3) were significantly lower in IBD TNF treated patients (162.6[1.7]) compared to IBD non TNF treated patients (325.2[1.3]), and healthy controls (325.2[1.3]), p<0.0001 (Figure 1). There was no difference between non-TNF treated patients including those on vedolizumab or IL12/23 compared to controls. Similarly there was a significant difference between anti-RBD IgG titres between TNF and non-TNF IBD patients at V3 but not when compared to controls (Figure 2). There was no difference in RBD IgG and anti-S1/2 antibodies between anti-TNF monotherapy and combination anti-TNF with immunomodulator. All IBD and healthy controls seroconverted at V3 (Figure 3). ConclusionTNF agents influence SARS-CoV-2 vaccine-induced antibody response in IBD patients, with lower anti-S1/2 IgG concentrations compared to non-TNF IBD patients and healthy controls. However, there was no difference in RBD IgG titres between controls and IBD patients overall. It is unclear whether these subtle differences in antibody response in IBD patients on TNF agents is biologically meaningful, as all groups seroconverted after second dose vaccination. Neutralising antibody and T cell data (CD4+/CD8+) from this study to come.

P577 Mucosal eosinophil abundance in non-inflamed colonic tissue predict response to vedolizumab induction therapy in inflammatory bowel disease

Abstract Background Vedolizumab has shown efficacy, safety and tolerability as treatment for patients with inflammatory bowel disease (IBD). However, vedolizumab induction therapy only shows clinical response and remission in roughly 55% and 30% of IBD patients, respectively. Vedolizumab binds and blocks migration of T-lymphocytes and eosinophils. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1, an eosinophil chemoattractant, regarding response to vedolizumab induction therapy. Methods 84 IBD patients treated within the University Medical Center Groningen (UMCG) (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. In a subset of 24 IBD patients (9 CD, 15 UC) histopathological data were analyzed for eosinophil counts in high power fields (hpf) in non-inflamed colon ascendens tissue prior to vedolizumab treatment. In another subset of 64 IBD patients, (28 CD, 36 UC) baseline serum eotaxin-1 was quantified prior to vedolizumab treatment. Clinical response or remission was defined as a decrease of the Harvey Bradshaw Index (HBI) for CD or Simple Clinical Colitis Activity Index (SCCAI) for UC together with physician’s global assessment (PGA). Serum eotaxin-1 was externally assessed as a biomarker for response to vedolizumab induction therapy in 100 IBD patients derived from the GEMINI 1 &amp; 2 trials. Results Baseline eosinophil mucosal count was significantly higher in vedolizumab induction therapy responders, compared to primary non responders (69[34–138] vs. 24[18–28] eosinophils/hpf respectively, P&amp;lt;0.01). Baseline serum eotaxin-1 levels in the UMCG cohort were significantly elevated in therapy responders, compared to primary non-responders (0.33 vs. 0.20 ng/mL, P&amp;lt;0.01). The final prediction model based on mucosal eosinophil count showed an area under the curve (AUC) of 0.90 and serum eotaxin-1 an adjusted AUC of 0.79 The optimal with balanced cut-off value for eosinophil count was &amp;gt; 30 eosinophils/hpf with a sensitivity of 90.9% and specificity of 92.3% (Youden’s index 0.83). Results derived from the GEMINI I &amp; II cohorts did not show any associations between eotaxin-1 levels and therapy response. Conclusion Mucosal eosinophil abundance in non-inflamed colon ascendens biopsies can predict vedolizumab induction therapy response in IBD patients. More studies are warranted to confirm these preliminary results and further investigate the additional value of eotaxin-1 regarding predicting vedolizumab therapy response.

Serum inter-alpha-trypsin inhibitor heavy chain 4 in patients with inflammatory bowel disease: correlation with disease risk, inflammation, activity, and its variation after treatment

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) plays vital roles in inflammatory and auto-immune diseases, but its correlations with disease risk and clinical features in inflammatory bowel disease (IBD) need further investigation. The present study intended to explore the correlation of ITIH4 with disease activity and inflammation, as well as its change after treatment in IBD patients. Totally, 40 active Crohn's disease (A-CD) patients, 40 clinical-remission CD (R-CD) patients, 40 active ulcerative colitis (A-UC) patients, 40 clinical-remission UC (R-UC) patients, and 40 health controls (HCs) were enrolled. ITIH4 in serum was assessed by ELISA. ITIH4 was lower in A-CD, R-CD, A-UC, and R-UC patients than in HCs (P < 0.001). Notably, ITIH4 reduced in A-CD patients than in R-CD patients (P = 0.017), and in A-UC patients compared with R-UC patients (P = 0.010). Besides, in A-CD patients, ITIH4 negatively correlated with tumor necrosis factor-alpha (TNF-α), interleukin (IL)-17A, IL-1β, C-reactive protein (CRP), and clinical disease activity index score (all P < 0.05). In A-UC patients, ITIH4 negatively correlated with TNF-α, IL-17A, IL-1β, IL-6, CRP, and Mayo score (all P < 0.05). However, in R-CD and R-UC patients, these correlations were less obvious than in A-CD and A-UC patients. ITIH4 was increased after treatment (all P < 0.05), and its expression at W12 after treatment was higher in response patients compared with no response patients in A-CD (P = 0.022) and A-UC groups (P = 0.038). ITIH4 correlates with IBD susceptibility, active risk, inflammation level, and its elevation after treatment relates to clinical response in IBD patients.

Rac1/pSTAT3 expression: A pharmacodynamic marker panel as a first step toward optimization of thiopurine therapy in inflammatory bowel disease patients.

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.

Hepatitis-B Vaccine Response in Inflammatory Bowel Disease Patients: A Systematic Review and Meta-analysis

Data on efficacy of hepatitis-B vaccine (HBV) in patients with inflammatory bowel disease (IBD) is limited. Our aim was to review the literature and perform meta-analysis of available studies to quantify efficacy of HBV in patients with IBD. We conducted a comprehensive search of several databases (inception to July 2020) to identify studies evaluating efficacy of HBV in patients with IBD. Random effects model was used to calculate the pooled rates and I2 percentage values were used to assess the heterogeneity. A total of 14 studies (2375 patients) were included. Four data sets were available from 2 studies that compared HBV response in patients with IBD against healthy controls. The pooled odds ratio of HBV response in IBD patients was 0.13 (95% CI, 0.05-0.33, P = 0.001). The pooled proportion of adequate immune response (AIR) was 64% (95% CI, 55-72.1, P = 0.003) from 13 data sets, and effective immune response (EIR) was 39.7% (95% CI, 30.7-49.5, P = 0.04) from 10 data sets. Patients with IBD on immunosuppression demonstrated significantly reduced HBV response as compared with general population.

Reversal of anti-drug antibodies against tumor necrosis factor inhibitors with addition of immunomodulators: A systematic review and meta-analysis.

The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients. We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model. Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36-94.38, I2= 60.77%). In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.

858 Reversal of Anti-Drug Antibodies Against Tumor Necrosis Factor Inhibitors With Addition of Immunomodulators: A Systematic Review and Meta-Analysis

INTRODUCTION: The presence of anti-drug antibodies (ADA) to tumor necrosis factor (TNF) inhibitors (infliximab or adalimumab) is one of the reasons for the diminished clinical response in patients with inflammatory bowel disease (IBD). To overcome the loss of response, dose escalation of TNF inhibitors or addition of immunomodulators (methotrexate or thiopurines) is considered before switching to other drugs due to limited therapeutic options. We conducted a systematic review and meta-analysis to assess the overall efficacy of immunomodulators (methotrexate or thiopurines) to reverse the loss of clinical response in IBD patients with TNF inhibitors antibodies. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Web of Science databases, Google Scholar and manual search of references (from inception through October 2018) to identify studies that reported the clinical response in patients with IBD on TNF inhibitors after the addition of immunomodulators (methotrexate or thiopurines). Clinical response was defined as improvement of symptoms, with either decrease or complete elimination of ADA against TNF inhibitors. The meta-analysis was performed using Der Simonian and Laird random effect model. RESULTS: A total of 4 studies reporting on 72 patients receiving either infliximab (27) or adalimumab (45) were included in our final meta-analysis. 49/72 (68%) patients received either thiopurines (30) or methotrexate (19). Total no of males: females were 32: 40. The mean age and follow up were 37.1 years and 13.5 months respectively. The overall pooled clinical response (Table 1) was 73.86% (95% CI = 47.36-94.38, I2 = 60.77%). Significant heterogeneity was noted in the studies included in our meta-analysis. CONCLUSION: In our limited meta-analysis, addition of immunomodulators to TNF inhibitors were shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long term multicenter studies are needed to further validate these findings

ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases.

Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed an association study using whole-exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multivariate logistic regression was performed to identify predictors. We found five candidate variants that were associated with primary nonresponse to infliximab (P<5×10-6 ). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P=6.49×10-7 ). We also identified the best genetic variant (rs9144, P=4.60×10-6 ) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P=2.10×10-5 ), concurrent azathioprine/6-mercaptopurine use, and bodyweight at the first infliximab use (<50kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P=0.001) were independently associated with the loss of response in patients with Crohn's disease. We identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients.

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Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease.

Loss of response to anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD) is often caused by anti-drug antibody formation with neutralisation of drug effect. Addition of an immunomodulator has been suggested to reduce immunogenicity, leading to regained response. To investigate whether addition of an immunomodulator to anti-TNF monotherapy could lead to anti-drug antibody suppression and regained clinical response in IBD patients. We retrospectively collected measurements of infliximab or adalimumab serum concentrations and anti-drug antibodies to identify anti-drug positive patients with loss response who were given an immunomodulator. Anti-drug antibodies against infliximab and adalimumab were detected in 98/376 (26%) and in 61/226 (27%) patients, respectively. Immunomodulators were given to 17/159 patients. Clinical response was recaptured in 6/10 patients receiving a thiopurine and in all (7/7) patients receiving methotrexate. In 7/8 patients on infliximab, serum concentrations increased (median 2.84 μg/mL; IQR: 1.19-4.98) and in 6/9 patients on adalimumab (median 3.10 μg/mL; IQR: 1.45-4.45). This was accompanied by a decrease in anti-drug antibodies to undetectable levels (median 11 months for both anti-TNF agents). In 23 patients, no immunomodulator was added but anti-TNF interval was shortened (17/23) or dosage was increased (6/23), which resulted in a clinical response in 10/17 and 2/6 patients, respectively. In 77% of IBD patients with loss of response due to immunogenicity, addition of immunomodulator resulted in undetectable anti-drug antibody levels, increased serum drug concentrations and regained clinical response. This strategy should be considered in this patient population before switching to other agents.

Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases.

The vaccination rate against hepatitis B virus (HBV) is low in inflammatory bowel disease (IBD) patients. The Consensus from the European Crohn's and Colitis Organisation on opportunistic infections recommends testing all IBD patients for HBV at diagnosis and vaccinating all HBV-negative patients. We compared the efficacy of HBV vaccine between IBD patients and healthy controls and investigated the impact of immunosuppressive therapy on vaccine response in IBD patients. IBD patients and healthy adult workers were vaccinated against HBV following a standard protocol (at 0, 1, and 6 months; Engerix B). The efficacy of vaccination was evaluated at 8 months by a titer of antibodies against hepatitis B surface antigen (anti-HBs). Among 164 participants (96 with IBD and 68 healthy workers), the level of anti-HBs was greater than 10 IU/l in 80.2 and 94.1% (P=0.0115) of IBD patients and healthy controls, respectively, and anti-HBs levels greater than 100 IU/l were seen in 45.8 versus 77.9% (P<0.0001) of IBD patients and healthy controls, respectively. The median level of anti-HBs was significantly higher in healthy controls (497.0±386.2) than in IBD patients (253.9±34.5) (P<0.0001). None of the baseline characteristics of IBD patients, including immunomodulators and antitumor necrosis factor therapy, influenced the vaccine response. In the multivariate analysis, ileal disease was the only factor associated with a lower response to the vaccine (odds ratio=3.2; 95% confidence interval=1.0-9.7; P=0.049). The response rate to HBV vaccination is significantly lower in IBD patients than in the general population. Immunosuppressive therapy for IBD did not influence the vaccine response.

Tu1315 Loss of Response in IBD Patients on Infliximab Treatment: Assay of Infliximab Trough Levels and Total Antibodies to Infliximab

Optimization of infliximab therapy in inflammatory bowel disease (IBD) patients who lose the clinical response is currently performed empirically. The assay of antibodies to infliximab (ATI) and infliximab trough levels (TL) could be helpful in the clinical decision. We collected sera from 102 IBD patients who were in maintenance treatment with infliximab. Fifty-five patients had experienced a loss of response (LOR) and most of them (45/55) had their infliximab dose already been optimized at 7.5 to 10 mg/kg. As a control group we studied 47 patients in stable clinical response. Blood was drawn for ATI, TL and C-reactive protein (CRP) assay immediately before the next infliximab infusion. We assayed ATI and TL by an ELISA kit (Immundiagnostik AG, Bensheim, FRG) that measures both free and bound antibodies even in the presence of circulating in fliximab. ATI results were expressed as arbitrary units (AU)/ml. TL were expressed as ug/ml. The subsequent clinical decisions were made blinded to ATI and TL levels. Clinical activity and CRP were also assessed after 12 months. Fifty-one patients had Crohn's disease and 51 had ulcerative colitis. Twenty-three were on concomitant immune modulators. In the whole patient population, median ATI were 24,5 AU/ml (IQR 7,4 to115,8) while median TL were 2,3 ug/ml (IQR 0 to 5,6). ATI and TL were negatively correlated (Spearman's rho -0,579, p 2,08 ug/ml for predicting clinical response at 12 months with 56,4% sensitivity and 70,8% specificity (AUC 0,628, 95% CI 0,527 to 0,722, p= 0,038). Among patients with LOR, 62% had ATI > 26,3 AU/ml, as compared to 32% of those maintaining the response (p=0,003 by Fisher's exact test). A significant correlation was detected between ATI and CRP levels both at baseline (Spearman's rho 0,218, p= 0,0287) and after 12 months (rho 0,284, p= 0,0043). Prospective studies will determine the utility of these cut off values in the management of LOR to infliximab in IBD.

In vitro sensitivity assays and clinical response to glucocorticoids in patients with inflammatory bowel disease

BackgroundGlucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, non-response can only be assessed empirically by observing continued disease activity. MethodsTo identify potential biomarkers of GC response, we retrospectively identified and recruited 18 GC-responsive and 18 GC-nonresponsive IBD patients. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohn's disease (CD), all previously treated with steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]). ResultsIn both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical GC response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical GC response in UC patients (P=0.009), but not in CD patients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical GC response across both diseases (P=0.005). ConclusionsWe show that inhibition of LPS stimulation is more strongly associated with clinical GC response in IBD patients than inhibition of PHA and α-CD3/α-CD28-mediated proliferation. These results support an important role of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response to GCs.

PWE-111 Higher Red Blood Cell Methotrexate Polyglutamates Correlate With Increased Disease Activity, And Are Useful In Assessing Adherence

IntroductionMethotrexate (MTX) is commonly used in patients with inflammatory bowel disease (IBD). Within red blood cells (RBC), MTX is activated by sequential addition of glutamic acid residues to form polyglutamates...

Sa1245 Gut Microbiota in IBD Patients With IBS Before and After 6 Weeks of Low FODMAP Diet

Background: Glucocorticoids (GCs) are steroid hormones used to induce remission in moderate-to-severe inflammatory bowel disease (IBD). A substantial fraction of patients do not respond to GC treatment and require alternate therapies or surgery. At present, nonresponse can only be assessed empirically by observing continued disease activity. Aim: To identify biomarkers of GC response in IBD patients and provide insights into the biological processes underlying variation in clinical response to GCs. Methods: 18 GC-responsive and 18 GC-nonresponsive IBD patients were retrospectively recruited from our IBD Center. This sample included 14 patients with ulcerative colitis (UC) and 22 patients with Crohn's disease (CD), all previously treated with oral or intravenous steroids. In peripheral blood mononuclear cells from each patient, we performed in vitro assays to measure GC inhibition of three different immune stimulants (phytohemagglutinin [PHA], α-CD3/α-CD28, and lipopolysaccharide [LPS]) controlling for age, gender, ethnicity, and current medications. Results: In both diseases, we found that inhibition of PHA-mediated T cell proliferation was significantly associated with clinical response (P=0.04). Inhibition of proliferation due to direct T cell receptor stimulation using α-CD3/α-CD28 was also significantly associated with clinical response in UC patients (P=0.009) (Figure 1), but not in CD patients (P=0.78). Interestingly, inhibition of LPS-mediated cytokine secretion showed the strongest association with clinical response across both diseases (P=0.005) (Figure 2). Conclusions: Extending on previously observed associations between inhibition of PHA and α-CD3/α-CD28-mediated proliferation and clinical response, we show that inhibition of LPS stimulation shows an even stronger association with clinical response to GCs in patients with IBD. These results are consistent with the importance of bacterial recognition and innate immunity in the etiology of IBD. This assay could be a powerful predictor of clinical response and future studies are needed in order to replicate these observations.