Adalimumab Maintenance Therapy Research Articles

P570 Efficacy and safety of Adalimumab in Very Early-onset IBD- A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN

Abstract Background Patients with very early onset inflammatory bowel disease (VEOIBD) often present with severe disease course and require escalation to biologics. Exclusion of pediatric patients from clinical trials lead to scarcity of efficacy and safety data on TNFa antagonists therapy in VEOIBD. We aimed to assess safety and efficacy of adalimumab (ADM) induction and maintenance therapy in patients with VEOIBD. Methods This was a retrospective study involving 31 sites affiliated with the IBD Porto Group and IBD Interest Group of ESPGHAN, as well as centers in North America. Demographic, clinical and laboratory data were collected from patients diagnosed with VEOIBD who commenced ADM therapy before 6 years of age between 2014 to 2023. Results We identified 77 VEOIBD patients with a median age at diagnosis of 2.6 years (interquartile range [IQR] 1.3–4.1), of whom 29 (38%) were diagnosed at age <2 years (infantile-onset IBD). Thirty-seven (48%) patients were diagnosed with Crohn’s disease, 25 (32%) with ulcerative colitis and 15 (20%) with IBD-unclassified. Five (9%) from those genetically tested were diagnosed with monogenic disease. Median age at initiation of ADM was 4.2 (IQR 2.8-5.1) years. Forty-four patients (57%) were Infliximab experienced, discontinued mainly due to pharmacokinetic (20 [45%]) and pharmacodynamic (13 [30%]) failures. At initiation of ADM, concomitant corticosteroids and immunomodulators were given in 37 (48%) and 29 (37%) patients, respectively. The median wPCDAI and PUCAI scores at baseline were 45 [37.5-60] and 45 [27.5-57.5], respectively. Median follow-up time was 85.4 (IQR 40.4-139.2) weeks. While patients with CD showed significant clinical improvement after 26 and 52 weeks (PCDAI decreased to 10 [0-33.4], p<0.001, and 10 [0-25], p<0.05, respectively), No significant improvement in PUCAI score was observed among patients with UC (Figure 1). Inflammatory markers and calprotectin showed a gradual decrease over time (Figure 1). Weight and Height Z scores did not differ significantly throughout the follow-up period. ADM discontinuation rates after 1 and 3 years were 40% and 65%, respectively, mainly due to primary non-response (14, 29.8%) and loss of response (19, 40.4%). Drug discontinuation rates were not dependent on concomitant immunomodulator treatment or ADM initiation or on age (less or above 3 years). Four patients (5.2%) developed severe infections, including a patient with TTC7A mutation who died following septic shock. Conclusion Adalimumab therapy was relatively safe and seemed more effective in young patients with Crohn’s disease, but not in those with ulcerative colitis. Durability was relatively low due to high rates of primary non-response and secondary loss of response.

Immunomodulator Withdrawal From Anti-TNF Therapy Is Not Associated With Loss of Response in Inflammatory Bowel Disease

The benefit of concomitant immunomodulators (thiopurines or methotrexate) in patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor α (anti-TNF) (infliximab or adalimumab) maintenance therapy is debated. We compared outcomes after immunomodulator withdrawal vs continuation of combination therapy. This was a retrospective cohort study in a general hospital and a tertiary referral center. We included adult IBD patients, receiving anti-TNF therapy for ≥4 months, plus an immunomodulator at baseline, between January 1, 2011, and January 1, 2019. The primary endpoints were loss of response (LOR) (ie, anti-TNF discontinuation because of disease activity) and anti-drug antibodies. Adjusted hazard ratios (aHRs) were calculated by mixed-effects Cox regression analysis. We included 614 treatment episodes of combination therapy in 543 individuals, yielding 1664 patient-years of follow-up. The immunomodulator was withdrawn in 296 (48.2%) episodes after 0.9 (interquartile range, 0.6-2.1) years, which was not associated with a higher risk of LOR (aHR, 1.08; 95% confidence interval [CI], 0.72-1.61), although anti-drug antibodies were detected more frequently (aHR, 2.14; 95% CI, 1.17-3.94), compared with continuation. Clinical remission at the time of withdrawal reduced the risk of LOR (aHR, 0.48; 95% CI, 0.25-0.93), while longer duration of combination therapy before withdrawal decreased the risk of anti-drug antibodies (HR per year, 0.56; 95% CI, 0.32-0.91). Higher prewithdrawal infliximab trough levels reduced the subsequent risks of anti-drug antibodies and LOR. Infliximab trough levels were lower after immunomodulator withdrawal (P= .01). Patients who withdrew the immunomodulator in this retrospective cohort were not at increased risk of LOR within the following 1-2 years, but an increase in anti-drug antibodies was observed. Our findings require prospective validation, preferably in adequately powered randomized controlled trials.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis.

Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40mg subcutaneous (sc) weekly or 80mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6years (interquartile range [IQR] 4.0-9.6) and 3.0years (IQR 0.9-9.4) in the SD group (log-rank test P=0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P=0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P=1.0). Results were similar in the propensity score-matched cohort. High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

Lengthening adalimumab dosing interval in quiescent Crohn’s disease patients: protocol for the pragmatic randomised non-inferiority LADI study

IntroductionAdalimumab is effective for maintenance of remission in patients with Crohn’s disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse...

Lower adalimumab trough levels are associated with higher bowel wall thickness in Crohn's disease.

In Crohn's disease, higher adalimumab trough levels and negative anti-adalimumab-antibodies associate with better clinical and endoscopic outcomes. Intestinal ultrasound has become a relevant non-invasive method to monitor treatment. However, data on the association between adalimumab levels and bowel wall thickness measured with ultrasound is limited. The purpose of this study was to examine the possible association between the sonographic transmural-thickness and adalimumab trough levels. This prospective observational cohort study was conducted at Sheba Medical Center in 2014-2018. Crohn's disease patients on adalimumab maintenance therapy with intestinal ultrasound performed within <30 days of trough level measurement were included. Associations between terminal ileum and colonic thickness, adalimumab levels and therapy retention were assessed. Fifty events of ultrasound with concomitant adalimumab trough level measurements in 44 Crohn's disease patients were included. Patients with trough level <3 μg/ml had significantly higher bowel wall thickness, both for terminal ileum (p = 0.04) and colon (p = 0.02). Thirty-two patients continued adalimumab therapy over one year. The adalimumab retention rate was higher among those with terminal ileum thickness <4 mm (p = 0.03). Lower adalimumab trough levels were associated with higher bowel wall thickness indicating poorer therapy outcome. Transmural thickness measurement with ultrasound may be a useful target for guiding biologic therapy in Crohn's disease.

A246 POPULATION WIDE STUDY OF THE EPIDEMIOLOGY AND OUTCOMES OF ANTI-TNF DOSE AUGMENTATION IN INFLAMMATORY BOWEL DISEASE

Abstract Background Inflammatory bowel disease (IBD) patients who experience loss of response to anti-tumor necrosis factor (anti-TNF) therapy are often treated with augmented doses of anti-TNF to recapture response. Despite this, factors associated with dose augmentation and treatment outcomes following dose augmentation remain largely undefined. Aims To examine the epidemiology of anti-TNF dose augmentation and determine the associated treatment outcomes among a province-wide cohort of anti-TNF treated IBD subjects. Methods The University of Manitoba Inflammatory Bowel Disease Epidemiological Database was used to identify patients receiving infliximab or adalimumab maintenance therapy for IBD in the Canadian province of Manitoba. Anti-TNF dose augmentation was defined as a ≥50% increase in anti-TNF dose or a shortening of dosing interval to ≤42 days for infliximab or ≤10 days for adalimumab. Anti-TNF failure was defined as corticosteroid use, IBD-related hospitalization, resective IBD surgery, or change in anti-TNF agent. Competing risks regression using a proportional subhazards model was used to determine the associations between dose augmentation, anti-TNF failure, anti-TNF discontinuation and a number of patient, disease, and treatment factors. Results 871 persons (624 Crohn’s disease (CD), 247 ulcerative colitis (UC)) using anti-TNF maintenance therapy were identified. Cumulative incidence of dose augmentation among continued users was 25.7% at 90 days, 52.3% at 1 year, and 72.8% at 5 years. Anti-TNF failure occurred in 261 of 575 dose augmented subjects, with corticosteroid use the most common failure-defining event. Failure of standard dose anti-TNF in the 90 days preceding dose augmentation was strongly associated with failure of dose augmentation (HR 2.98 (2.27–3.93); p&amp;lt;0.0001). Persons with CD were less likely to receive corticosteroids but more likely to switch anti-TNF agents than persons with UC. Conclusions Rates of adverse IBD outcomes remain high after dose augmentation, particularly when dose augmentation is undertaken shortly after (or in response to) one of these adverse events. Our data suggest that dose augmentation may not be as effective as uncontrolled observational studies have indicated. Funding Agencies None

P092 COMPARISON OF INFLIXIMAB AND ADALIMUMAB CONCENTRATIONS BETWEEN THE ENZYME-LINKED IMMUNOSORBENT ASSAY AND THE HOMOGENEOUS MOBILITY SHIFT ASSAY (HMSA) IN INFLAMMATORY BOWEL DISEASE: AN UPDATE FOLLOWING IMPLEMENTATION OF CORRECTIVE MEASURES FOR THE HMSA

Abstract Background and aims We previously showed a discrepancy between a commercially available enzyme-linked immunosorbent assay (ELISA) and the homogenous mobility shift assay (HMSA) for both infliximab and adalimumab concentrations in patients with inflammatory bowel disease (IBD).1 Based also on the results of this study, Prometheus Laboratories initiated a comprehensive review of their HMSA assays and found that there was an upward drift for both infliximab and adalimumab over a 2-year period, including when our study was being performed. Prometheus corrected the errant values and reported the revised drug concentrations to physicians. We aimed to compare these two assays following the implementation of these corrective measures. Methods Samples from patients with IBD either on infliximab or adalimumab maintenance therapy were prospectively evaluated using both ELISA (InformTx™, Inform Diagnostics) (for research purposes) and the HMSA (ANSER™, Prometheus Laboratories) (performed clinically). Comparison of drug concentrations between assays was performed as previously described.1 Results In total 74 samples were analysed (infliximab, n=45; adalimumab, n=29). Drug concentrations (median [interquartile range, IQR]) were still significantly higher when measured by the HMSA compared to ELISA for foth infliximab (9 [7.1–12.4] vs. 5.7 [4.8–9] μg/ml; p&amp;lt;0.001, respectively) and adalimumab (12.9 [10.3–16.9] vs. 10.6 [8.6–14] μg/ml; p=0.036, respectively). The correlation of infliximab and adalimumab concentrations between assays is depicted in Figure 1. Agreement between assays was moderate [ICC: 0.658; 95% confidence interval (CI): -0.080 to 0.892; p&amp;lt;0.001] for infliximab and strong (ICC = 0.826, 95%CI: -0.066 to 0.949, p&amp;lt;0.001) for adalimumab. A Bland–Altman plot of infliximab and adalimumab concentrations to compare the two assays is shown in Figure 2. Qualitative agreement in drug concentration status (therapeutic or sub-therapeutic) was only minimal between assays using &amp;gt;5 μg/ml (K = 0.299, p=0.005), &amp;gt;7 μg/ml (K = 0.303, p=0.005) or &amp;gt;10 μg/ml (K = 0.323, p=0.003) as therapeutic drug concentrations for infliximab, while for adalimumab was weak using &amp;gt;10 μg/ml as therapeutic drug concentrations (K = 0.437, p=0.004), although overall agreement using either &amp;gt;5 or &amp;gt;7 μg/ml as therapeutic drug concentrations was 97%. Conclusions These data suggest that although the correlation between the ELISA and the HMSA was very good for both infliximab and adalimumab it is difficult to compare absolute drug concentrations. Until commercial assays are properly cross-validated and standardized, assay-dependent drug concentration thresholds may need to be applied to better interpret therapeutic drug monitoring results and it is advisable that patients are monitored with the same assay. 1Inflamm Bowel Dis. 2019 Sep 27. https://doi.org/10.1093/ibd/izz202. [Epub ahead of print]

Long-term Outcomes of Adalimumab Therapy in Korean Patients with Ulcerative Colitis: A Hospital-Based Cohort Study.

Background/AimsStudies on long-term outcomes of adalimumab therapy in non-Caucasian patients with ulcerative colitis (UC) are lacking.MethodsWe analyzed long-term outcomes of Korean UC patients treated with adalimumab at the Asan Medical Center, Seoul, Korea.ResultsBetween July 2013 and October 2018, adalimumab therapy was started in a total of 100 patients with UC (65 males [65.0%]; median age, 39.5 years [interquartile range, 23.3 to 49.8 years]; and median disease duration, 3.0 years [interquartile range, 1.0 to 7.0 years]). The median duration of adalimumab therapy was 13.5 months (interquartile range, 4.0 to 32.0 months). Eight of 100 patients (8.0%) received induction therapy only, four (4.0%) of whom ultimately underwent colectomy. Of 92 patients who received adalimumab maintenance therapy, 30 (30.0%) stopped adalimumab therapy due to loss of response, and one patient (1.0%) was lost to follow-up. Among the 92 patients who received adalimumab maintenance therapy, the cumulative proportions of patients remaining on adalimumab maintenance therapy were 70.0% at 1 year and 48.9% at 5 years. High partial Mayo score after 8 weeks of adalimumab therapy (hazard ratio [HR], 1.217; 95% confidence interval [CI], 1.040 to 1.425; p=0.014) and a history of exposure to two biologic agents before adalimumab therapy (HR, 4.722; CI, 1.033 to 21.586; p=0.045) were predictors of adalimumab discontinuation.ConclusionsLong-term outcomes of adalimumab therapy in Korean UC patients appear to be comparable to those in previously published Western studies. Furthermore, previous exposure to multiple biologic agents before adalimumab therapy and disease activity after 8 weeks of adalimumab therapy were predictors of adalimumab discontinuation.

Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2)

The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn's disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596). Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6months with ADA (40mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, "continue" (Con) or "discontinue" (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety. Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group. Continuation of thiopurines > 6months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

Concerns and Side Effects of Azathioprine During Adalimumab Induction and Maintenance Therapy for Japanese Patients With Crohn's Disease: A Subanalysis of a Prospective Randomised Clinical Trial [DIAMOND Study

Combining a thiopurine with the human anti-tumour necrosis factor-α monoclonal antibody adalimumab for Crohn's disease [CD] treatment is controversial with regard to efficacy and safety. By conducting a subanalysis of a multicentre, randomised, prospective, open-label trial [the DIAMOND study, UMIN registration number 000005146], we studied the risk of discontinuation of thiopurine in combination with adalimumab. In the preceding DIAMOND study, we analysed the: [i] timing and reasons for dropout in the monotherapy group and combination group; [ii] risk factors for dropout in the combination group. There was no significant difference in the dropout rate up to Week 52 between the monotherapy group and combination group [p = 0.325]. The main reason for study dropout was active CD in the monotherapy group, whereas it was adverse effects in the combination group [Fisher's exact test, p <0.001]. Kaplan-Meier analyses revealed significantly earlier dropout in the combination group [log-rank test, p = 0.001]. Multivariable analysis revealed low body weight to be a risk for dropout due to adverse effects in the combination group. Combination of azathioprine with adalimumab resulted in dropout in the early stage of the study due to side effects of azathioprine, in comparison with late dropout due to active CD in the adalimumab monotherapy group.

P319 Trough levels of adalimumab better correlate with combined mucosal and transmural healing than clinical remission in Korean patients with Crohn’s disease on adalimumab maintenance therapy

P319 Trough levels of adalimumab better correlate with combined mucosal and transmural healing than clinical remission in Korean patients with Crohn’s disease on adalimumab maintenance therapy

Maintenance Adalimumab Concentrations Are Associated with Biochemical, Endoscopic, and Histologic Remission in Inflammatory Bowel Disease.

A treat-to-target therapeutic approach is emerging as the new standard of care for treating inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). We aimed to investigate the association of serum adalimumab concentrations during maintenance therapy with biochemical, endoscopic, and histologic remission in IBD. This retrospective multicenter study included consecutive IBD patients on adalimumab maintenance therapy who had a C-reactive protein (CRP) within 1week and/or endoscopic evaluation within 12weeks of therapeutic drug monitoring between July 2013 and December 2016. Biochemical remission was defined as a normal CRP (≤ 5mg/L). Endoscopic remission was defined as the absence of any ulceration/erosion or a Rutgeerts score of ≤ i1 for patients with an ileocolonic resection for CD and a Mayo endoscopic score of ≤ 1 for UC. Histologic remission was defined as the absence of any sign of active inflammation. Adalimumab concentrations were measured using the homogeneous mobility shift assay. Ninety-one CRP levels and 72 colonoscopies from 98 IBD patients [CD: n = 72 (73%)] were evaluated. Based on receiver operating characteristic analyses, we identified an adalimumab concentration threshold of 11.8, 12, and 12.2μg/mL in CD and 10.5, 16.2, and 16.2μg/mL in UC to stratify patients with or without biochemical, endoscopic, or histologic remission, respectively. Adalimumab concentrations ≥ 12μg/mL (OR 8; 95% CI 2-31.9; p = 0.003) and ≥ 12.2μg/mL (OR 9.6; 95% CI 1.7-56.1; p = 0.012) were independently associated with endoscopic and histologic remission in CD, respectively. This study demonstrates that higher maintenance adalimumab concentrations are associated with objective therapeutic outcomes in IBD.

Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn’s Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials

Background and AimsIn the 4-week GAIN clinical trial, adalimumab was efficacious in inducing remission in patients with moderate-to-severe Crohn’s disease [CD] who had prior loss of response/intolerance to infliximab. The efficacy and safety of adalimumab in these patients are reported here for up to 96 weeks or for 3 years, respectively, in the ADHERE open-label extension study.MethodsPatients who completed GAIN could enrol in ADHERE and receive open-label adalimumab 40 mg every other week. Efficacy variables included clinical response (Crohn’s Disease Activity Index [CDAI] decrease from baseline ≥70/≥100 points [CR-70/CR-100]) and remission [CDAI<150], steroid discontinuation and fistula remission [absence of drainage]. Data were reported using hybrid non-responder imputation [hNRI], last observation carried forward and as-observed analysis. Subgroup analyses were performed by randomized group in GAIN and by Week 4 efficacy in GAIN. Safety was also assessed.ResultsA total of 310 patients from GAIN enrolled in ADHERE. CR-70, CR-100 and remission rates at Week 96 were 39.0%, 35.5%, and 26.5% [hNRI], respectively. Of the patients with CR-70 response or remission at Week 4 of GAIN, 45.5% and 44.4% [hNRI], respectively, maintained the effect at Week 96. Steroid discontinuation and steroid-free remission rates increased from Week 12 to 96 in patients using corticosteroids at GAIN baseline.ConclusionsLong-term adalimumab maintenance therapy led to sustained clinical remission and response, and steroid discontinuation in a considerable proportion of patients with CD previously treated with infliximab. No new safety signals were observed in this patient population.

P048 HISTORY OF CYTOMEGALOVIRUS COLITIS IS ASSOCIATED WITH POOR LONG-TERM OUTCOMES IN ADALIMUMAB THERAPY IN KOREAN PATIENTS WITH ULCERATIVE COLITIS: A HOSPITAL-BASED COHORT STUDY

Studies regarding long-term outcomes of adalimumab treatment in non-Caucasian patients with ulcerative colitis (UC) are still lacking. We analyzed long-term outcomes of Korean UC patients on adalimumab treatment in Asan Medical Center, Korea. Between July 2013 and June 2017, adalimumab treatment was commenced on in 72 patients; 49 males (68.1%), median age 40.5 years (Interquartile range [IQR], 24.25–50.00), and median disease duration 39.5 months (IQR, 22.00–85.00) at initiation of adalimumab. Twelve patients (16.7%) had a history of cytomegalovirus colitis within 3 months prior to starting adalimumab. Median duration of adalimumab therapy was 10.50 months (IQR, 2.00–26.75). Seventeen out of 72 patients (23.6%) were primary non-responders, and 7 out of those (9.7%) finally received colectomy. Out of 55 patients who received scheduled adalimumab maintenance therapy, 9 (16.4%) and 3 (5.5%) stopped adalimumab treatment due to loss of response and patients’ preference for discontinuation/loss to follow-up, respectively. Adalimumab dose intensification was required in 22 (40.0%) and corticosteroid rescue therapy was needed in 15 (27.3%) out of 55 patients during adalimumab maintenance therapy. The cumulative proportion of patients without adalimumab discontinuation was 61.0% at 1 year and 56.5% at 3 years among 72 patients who received adalimumab treatment more than once, and 80.1% at 1 year and 74.1% at 3 years among 55 patients who received adalimumab maintenance therapy. History of cytomegalovirus colitis within 3 months prior to starting adalimumab treatment was turned to be a predictor of adalimumab discontinuation (hazard ratio, 3.976; 95% confidence interval, 1.149–13.755; p = 0.029). Long-term outcomes of adalimumab treatment in Korean UC patients appears to be comparable to Western studies. Furthermore, a recent history of cytomegalovirus colitis was a predictor for adalimumab discontinuation.

P415 Dose escalation of adalimumab and related prognostic factors in patients with Crohn's disease treated with adalimumab maintenance therapy: A single-centre, five-year cohort study

P415 Dose escalation of adalimumab and related prognostic factors in patients with Crohn's disease treated with adalimumab maintenance therapy: A single-centre, five-year cohort study

P048 HISTORY OF CYTOMEGALOVIRUS COLITIS IS ASSOCIATED WITH POOR LONG-TERM OUTCOMES IN ADALIMUMAB THERAPY IN KOREAN PATIENTS WITH ULCERATIVE COLITIS: A HOSPITAL-BASED COHORT STUDY

Studies regarding long-term outcomes of adalimumab treatment in non-Caucasian patients with ulcerative colitis (UC) are still lacking. We analyzed long-term outcomes of Korean UC patients on adalimumab treatment in Asan Medical Center, Korea. Between July 2013 and June 2017, adalimumab treatment was commenced on in 72 patients; 49 males (68.1%), median age 40.5 years (Interquartile range [IQR], 24.25-50.00), and median disease duration 39.5 months (IQR, 22.00-85.00) at initiation of adalimumab. Twelve patients (16.7%) had a history of cytomegalovirus colitis within 3 months prior to starting adalimumab. Median duration of adalimumab therapy was 10.50 months (IQR, 2.00-26.75). Seventeen out of 72 patients (23.6%) were primary non-responders, and 7 out of those (9.7%) finally received colectomy. Out of 55 patients who received scheduled adalimumab maintenance therapy, 9 (16.4%) and 3 (5.5%) stopped adalimumab treatment due to loss of response and patients’ preference for discontinuation/loss to follow-up, respectively. Adalimumab dose intensification was required in 22 (40.0%) and corticosteroid rescue therapy was needed in 15 (27.3%) out of 55 patients during adalimumab maintenance therapy. The cumulative proportion of patients without adalimumab discontinuation was 61.0% at 1 year and 56.5% at 3 years among 72 patients who received adalimumab treatment more than once, and 80.1% at 1 year and 74.1% at 3 years among 55 patients who received adalimumab maintenance therapy. History of cytomegalovirus colitis within 3 months prior to starting adalimumab treatment was turned to be a predictor of adalimumab discontinuation (hazard ratio, 3.976; 95% confidence interval, 1.149-13.755; p = 0.029). Long-term outcomes of adalimumab treatment in Korean UC patients appears to be comparable to Western studies. Furthermore, a recent history of cytomegalovirus colitis was a predictor for adalimumab discontinuation.

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn's disease.

Background:Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity.Methods:In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn’s disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3–8 mg/liter for infliximab and 5–12 mg/liter for adalimumab.Results:Of 210 patients included, 137 (65.2%) had Crohn’s disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn’s disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn’s disease) of patients. In Crohn’s disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn’s disease were also associated with higher CRP concentrations compared with therapeutic concentrations.Conclusions:The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn’s disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054]

Long-Term Outcomes of Adalimumab Treatment in 254 Patients with Crohn's Disease: A Hospital-Based Cohort Study from Korea.

Large-scale studies regarding the long-term outcomes of adalimumab (ADA) treatment in Asian patients with Crohn's disease (CD) are still scarce. We retrospectively analyzed the long-term outcomes of ADA treatment in Korean CD patients who commenced on scheduled ADA treatment at Asan Medical Center between November 2008 and July 2016. Clinical response was defined as maintaining ADA treatment without dose intensification (DI) and/or major abdominal surgery (MAS). Of the 254 patients who received at least two doses of ADA at 2-week intervals as induction therapy, 250 patients (98.4%) showed an initial favorable response by week 4. Among responders, 243 patients were followed up for longer than 4weeks and were included for further analysis. The median duration of ADA maintenance therapy was 19.4months. At the last follow-up, 45 patients (18.5%) required DI after a median of 16.8months and 31 (12.8%) required MAS after a median of 8.9months. Finally, 161 patients (66.3%) were still receiving ADA without DI and/or MAS. The cumulative probability of maintaining ADA without DI and/or MAS was 81.1% at 1year, and 36.5% at 5years. Secondary loss of response to previous infliximab (P=0.001) and elevated baseline C-reactive protein at starting ADA treatment (P=0.008) were identified as independent predictors of a poor response to ADA treatment using multivariate regression analysis. The long-term outcome of ADA treatment in a real-life cohort of Korean patients with CD appears to be comparable to that reported in previously published Western studies.

Risk factors for recurrence of Crohn's disease requiring surgery in patients receiving post-operative anti-tumor necrosis factor maintenance therapy.

Objectives: Anti-tumor necrosis factor (TNF) antibodies have shown efficacy in the prevention of recurrence of Crohn's disease after intestinal resection. However, some patients develop surgical recurrence despite this therapy. We aimed to evaluate the risk factors for recurrence of Crohn's disease requiring surgery while receiving post-operative anti-TNF therapy. Methods: We performed a retrospective evaluation of 164 patients who had received post-operative anti-TNF maintenance therapy between 2002 and 2016. We classified Crohn's disease-related re-operation as surgical recurrence and analyzed its risk factors using the Cox proportional hazard model. Results: Of the 164 participants, 128 had received infliximab and 36 had received adalimumab maintenance therapy. We obtained follow-up data over a mean of 60.2 months. The proportion of patients with surgical recurrence at 5 years was 14.9%. The only independent risk factor for surgical recurrence, which we identified was post-operative smoking habit (odds ratio, 5.03; 95% CI, 1.14-12.8; P=0.033). Conclusions: Post-operative smoking may be a significant risk factor for post-operative surgical recurrence of Crohn's disease while receiving anti-TNF maintenance therapy.