anti-TNF Dose Research Articles

Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn’s disease (REMODEL-CD): study protocol for a multicentre, open-label, pragmatic clinical trial in the USA

IntroductionThe only biologic therapy currently approved to treat moderate to severe Crohn’s disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically...

A221 AZATHIOPRINE DOSING THRESHOLD IN ANTI-TNF COMBINATION THERAPY FOR MINIMIZING IMMUNOGENICITY AND OPTIMIZING TREATMENT EFFICACY FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. A RETROSPECTIVE COHORT STUDY

Abstract Background Reported rates of anti-drug antibody (ADA) formation to tumor necrosis factor-a antagonists (anti-TNF) range from 20-75%. One way to reduce the risk of ADA formation is to combine a second immune-suppressing agent such as azathioprine (AZA) with the anti-TNF agent, known as combination therapy. However, it is unknown if the risk of combination therapy, including the additive risk of AZA and anti-TNF side effects, could be reduced by exposing individuals with inflammatory bowel disease (IBD) to the lowest dose of azathioprine while still maintaining the beneficial effect of ADA prevention. Aims To identify the minimum dose of AZA needed to prevent ADA formation to anti-TNF agents in individuals with IBD receiving combination therapy. We also assessed the occurrence of adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Methods A retrospective cohort study is ongoing in adult participants with IBDreceiving either infliximab or adalimumab in combination with AZA. Patients are divided based on their AZA dosage (low dose group, AZA ampersand:003C2mg/kg/day versus standard dose group, AZA 2mg/kg/day). All participants will be followed for 1 year and observed for the occurrence of ADA formation, adverse drug events, treatment loss of response, treatment discontinuation and the need for treatment dose escalation. Results To date, 48 participants are currently included (low dose, n=29; standard dose, n=19). 42 are on Infliximab and 6 are on Adalimumab. The occurrence of ADA was 17.4% in the low dose group and 20% in the standard dose group (pampersand:003E0.99). More participants lost response to treatment and discontinued anti-TNF therapy in the standard dose group (n=7/19, 36.8%) versus the low-dose group (n=8/29, 27.6%, p=0.54). More participants in the low-dose group received anti-TNF dose escalation (n= 20/29,68.9%) compared to the standard dose group (n=6/19, 31.6%, p=0.017). Adverse events, to Anti-TNF was seen in (n=3/19, 15.7%) in the standard dose group, in comparison to (n=4/29, 13.79%, pampersand:003E0.99) in the low dose group. Adverse events to AZA were surprisingly higher in the low dose group (n=14/29, 48.3%) while in the standard dose, it was (n=5/19, 26.3%, p=0.14). Conclusions The preliminary result of the study suggests that there is no significant difference in anti-drug antibody formation between standard and low doses of azathioprine in combination with anti-TNF therapy, in addition, data showed significant lower rates of Anti-TNF discontinuation and loss of response to treatment in low Azathioprine dose group. Completion of the study will help further define if low-dose AZA can be used for ADA prevention in anti-TNF combination therapy without compromising important clinical outcomes. Funding Agencies None

Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies

Objective Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). Methods Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. Results Two-hundred-and-fifty-five IBD patients (206 Crohn’s disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (−22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. Conclusions Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.

Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients

Background and aims Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. Methods Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. Results The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). Conclusion Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.

A205 EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD EOSINOPHILS AND DRUG RESPONSE IN CROHN'S DISEASE: CONTINUING ANALYSIS

Abstract Background Th2 cytokines, IL-5 and IL-13 enhance peripheral and mucosal eosinophil survival, recruitment and degranulation, facilitating inflammation in Crohn's Disease. In a preliminary analysis, peripheral eosinophilia (PBE) is seen to have an association with rates of steroid response and anti-TNF response in CD patients. Participants with high PBE (&amp;gt; 200 cells/μL) appear to be more steroid-responsive but less responsive to Th1-targeting anti-TNF therapies. We hypothesize the pattern of PBE at CD diagnosis can help identify distinct subsets within a larger CD population and correlate with response to treatments such as prednisone or anti-TNFs. Purpose We aim to evaluate the pattern of PBE of CD patients at time of diagnosis (prior to drug exposure) and with each subsequent treatment; and if baseline PBE or any changes seen with drug exposures are predictive of treatment response. Method A retrospective cohort study is ongoing with CD patients exposed to glucocorticoids and an anti-TNF seen at 3 hospitals affiliated with University of Western Ontario. Patients were identified using administrative databases and reviewed for biochemical data (complete blood count) and disease activity (Harvey Bradshaw Index) at baseline, before and after each drug exposure. Participants were classified as having high PBE (eosinophils&amp;gt;200 cells/μL) versus low PBE (eosinophils &amp;lt;200 cells/μL). To date, 350 patients have been screened. Subgroup analyses of PBE &amp;gt; 300 cells/μL, and differences between female and male patients will be carried out. Result(s) 46 of 200 CD patients are included in the continuing analysis with a mean age of 45 years. 26 had PBE &amp;gt;200 cells/μL at baseline and 20 did not. The median number therapies used was 4 (IQR=0.75). All received glucocorticoids followed by an anti-TNF. There was no difference in the occurrence of hospitalization or surgery between the two groups. Overall 50% participants with high PBE &amp;gt;200 and &amp;gt;300 cells/μL had clinical response to glucocorticoid exposure, seen as a 3-point decrease in HBI compared to 45%, 47% in the low PBE cohort (n=13/26 vs. n=9/20 p=0.77; n=6/12 vs. n=16/34 p=1.0 respectively). With subsequent anti-TNF exposure, PBE rebounded in 7 participants. 36% patients in the high PBE group required anti-TNF dose escalation versus 24% in the low PBE group (n=9/25 vs. n=5/21, p=0.52). The proportion of patients with anti-TNF discontinuation was similar in both groups (high PBE 19.2%, n=5/26 vs. low PBE 15%, n=3/20, p=1.0). Men had higher steroid response rates compared to women in both high and low PBE groups (n=6/8 vs. n=8/18 p=0.21; n=4/9 vs. 4/11 p=1.0 respectively). Conclusion(s) Peripheral eosinophilia is seen in varying degrees in CD patients. Participants with high PBE are more steroid-responsive. High PBE patients overall were less responsive to anti-TNF therapies, requiring more dose-escalation and discontinued anti-TNF treatment. Completion of this study will help clarify the association between PBE in CD and treatment response. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease

PurposeLoss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD.MethodsIn this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR.ResultsFollowing immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68–1.00) for regaining clinical remission, 0.87 (0.71–1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10−4).ConclusionImmunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

P672 Switching out of class or to another anti-TNF agent is the most effective strategy in IBD patients with immunogenicity against anti-TNF antibodies

Abstract Background Immunogenicity to anti-TNF agents is associated with loss of response in inflammatory bowel disease (IBD). However, the efficacy of different strategies to restore favourable pharmacokinetics and/or clinical response upon the detection of anti-drug antibodies (ADA) has not been widely studied. We evaluated the success of different strategies leading to clinical remission with ADA disappearance (in patients continuing the same anti-TNF), in patients with IBD. Methods IBD patients with ADA to infliximab or adalimumab were identified through an electronic database search at a single tertiary centre between 2004 and 2021. ADA were measured using a drug-sensitive assay at Sanquin laboratories. Data concerning clinical, biochemical and endoscopic activity, medication and surgery were retrospectively and systematically collected by reviewing clinical records. Criteria for success of a strategy were clinical remission 1 year after ADA detection without further change in strategy combined with disappearance of ADA (in patients continuing the same anti-TNF). Results Two-hundred-and-fifty-five IBD patients (206 Crohn’s disease, 46 ulcerative colitis, 3 IBD-unclassified, 149 female) were included, 129 patients were diagnosed to have ADA against infliximab and 126 against adalimumab. At baseline, median ADA titer was 77 AU/ml (IQR 25-350), 50.2% of patients were in clinical remission. Groups were as follows: 1) 81/255 (32%) conservative management, 2) 102/255 (40%) optimization of the same anti-TNF, 3) 72/255 (28%) switch to another anti-TNF or biological class. Switch to another anti-TNF or out of class was the most successful strategy in terms of improvement of clinical remission (from 19.4% at ADA detection to 69.4% at 1 year, p&amp;lt;0.001). Patients that continued with the same dose anti-TNF or discontinued all biological therapy after ADA detection were often in clinical remission at baseline, but deteriorated significantly in the following year (22.7%, P=0.004). Anti-TNF dose intensification with concomitant addition/optimisation of immunomodulators was the fastest (median 3 months (IQR 2-4.5), p=0.004) and most effective (in 73% of these patients, p=0.007) strategy to suppress ADA to undetectable levels compared to anti-TNF dose intensification or immunomodulator optimization alone. Conclusion Switching to another anti-TNF or out of class switch is the most successful strategy to regain and maintain clinical remission upon detection of ADA. Intensification of anti-TNF dosing with concomitant optimisation of immunomodulatory therapy is the fastest strategy to suppress ADA.

P798 Understanding anti-TNF treatment failure: mechanisms and management of loss of response to anti-TNF therapy, three-year data from the PANTS study

Abstract Background PANTS (Personalised Anti-TNF Therapy in Crohn’s disease) is a prospective observational UK-wide study investigating the effectiveness of infliximab (IFX) and adalimumab (ADL) in active luminal Crohn’s disease. Here we report remission rates through three years of follow up; rates of and the factors that predicted loss of response (LOR); and the effect of dose intensification on drug persistence. Methods Remission was defined as CRP of ≤3 mg/L and HBI of ≤4 points (sPCDAI ≤15 in children), without corticosteroid therapy or exit for treatment failure. LOR was defined in patients who initially responded to anti-TNF therapy at week 14 and continued in the PANTS extension, by symptomatic IBD activity that warranted an escalation of corticosteroids, immunomodulatory or anti-TNF therapy, resectional surgery, or exit due to adverse events. The effect of dose intensification at the time of LOR on drug persistence was stratified by optimal anti-TNF drug level (IFX 7, ADL 12) (mg/L) and presence of antibodies (anti-IFX 9, anti-ADL 6) (AU/mL), measured using IDKmonitor® ELISA assays. Results Between March 2013 and July 2016, 1610 patients were included in PANTS: 358/955 (37%) treated with IFX (221/358 [62%] originator and 137/358 [38%] with biosimilar) and 187/655 (29%) treated with ADL, who had not exited for treatment failure at the end of year 1, opted to enrol in the extension. Overall, 41.8%, 39.4%, and 41.3% of IFX- and 38.2%, 39.7%, and 39.2% of ADL-treated patients were in remission at year 1, 2 and 3, respectively. For both drugs, we observed a dose response association between week 14 drug concentration and remission status at the later timepoints (A). 34.3%, 54.0%, and 60.3% of IFX-, and 31.9%, 47.3%, and 69.0% of ADL-treated patients lost response at year 1, 2 and 3, respectively. Multivariable regression analyses showed that low drug concentration was the major independent risk factor associated with LOR for both drugs (B). In patients who developed immunogenicity, factors associated with subsequent drug clearance were lower week 14 drug level (p&amp;lt;0.01), non-immunomodulator use (p=0.04), and obesity (p&amp;lt;0.01), but not carriage of HLA-DQA1*05 (p&amp;lt;0.34). In the setting of LOR (n = 686 episodes), 42% patients had their anti-TNF dose intensified and 29% exited the study without further action (C). Compared to patients who experienced LOR with optimal drug levels, dose intensification was associated with lower rates of drug persistence in patients with immunogenic-pharmacokinetic and non-immunogenic pharmacokinetic treatment failure in patients treated with IFX, but not ADL (D). Conclusion Long term remission was observed in about 40% of patients treated with IFX and ADL. Loss of response and non-remission was predicted by low drug levels.

Stringent screening strategy significantly reduces reactivation rates of tuberculosis in patients with inflammatory bowel disease on anti-TNF therapy in tuberculosis endemic region.

Anti-tumor necrosis factor (anti-TNF) therapy use in patients with inflammatory bowel disease (IBD) leads to an increased risk of tuberculosis (TB) reactivation despite latent tuberculosis (LTB) screening, especially in TB endemic regions. We evaluated the effect of stringent screening strategy and LTB prophylaxis on TB reactivation. We performed an ambispective comparison between patients who received anti-TNF therapy after January 2019 (late cohort) and between Jan 2005 and Jan 2019 (early cohort). Late cohort patients were subjected to stringent screening criteria which included all: history of past TB/recent contact with active TB, chest X-ray, CT (computed tomography) chest, IGRA (interferon-gamma release assay), TST (tuberculin skin test), and if any positive were given chemoprophylaxis. A cohort comparison was done to evaluate for risk reduction of TB following the stringent screening strategy. One hundred seventy-one patients (63: ulcerative colitis/108: Crohn's disease, mean age diagnosis: 28.5±13.4years, 60% males, median follow-up duration after anti-TNF: 33months [interquartile range: 23-57months]) were included. Among the 112 in the early cohort, 29 (26%) underwent complete TB screening, 22 (19.6%) had LTB, 10 (9%) received chemoprophylaxis, and 19 (17%) developed TB. In comparison, in the late cohort, 100% of patients underwent complete TB screening, 26 (44%) had LTB, 23 (39%) received chemoprophylaxis, and only 1(1.7%) developed TB (p<0.01). On survival analysis, patients in early cohort had a higher probability of TB reactivation compared with the late cohort (HR: 14.52 (95% CI: 1.90-110.61 [p=0.01]) after adjusting for gender, age at anti-TNF initiation, concomitant immunosuppression, anti-TNF doses, and therapy escalation. The high risk of TB reactivation with anti-TNF therapy in TB endemic regions can be significantly mitigated with stringent LTB screening and chemoprophylaxis.

A163 EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD EOSINOPHILS AND DRUG RESPONSE IN CROHN’S DISEASE: A PRELIMINARY REPORT

BackgroundTh1, Th2, and Th17 immune pathways are variably activated in inflammatory bowel disease (IBD). The degree to which pathway having a more dominant role in propagating Crohn’s disease (CD) is not considered when selecting a treatment strategy. Th2 cytokines, IL-5 and IL-13 enhance eosinophil survival, recruitment and degranulation, facilitating inflammation. Mucosal eosinophilia has been documented in CD and its presence is a surrogate marker of Th2 pathway activation. Peripheral eosinophilia has an established role in asthma to help prognosticate treatment response to Th2-cytokine-specific therapies. We hypothesize the pattern of peripheral blood eosinophils (PBE) at CD diagnosis will identify distinct subsets within a larger CD population and correlate with response to treatments such as prednisone or anti-TNFs.AimsWe aim to evaluate the pattern of PBE of CD patients at time of diagnosis (prior to drug exposure) and with each subsequent treatment; and if baseline PBE or any changes seen with drug exposures are predictive of treatment response.MethodsA retrospective cohort study is ongoing with CD patients exposed to glucocorticoids and an anti-TNF seen at one of 3 hospitals affiliated with University of Western Ontario. Patients were identified using administrative databases and reviewed for biochemical data (complete blood count) and disease activity (Harvey Bradshaw Index) at baseline as well as before and after each drug exposure. Participants were classified as having high PBE (eosinophils >200 cells/μl) versus low PBE (eosinophils <200 cells/μl).ResultsTo date,10 of 200 CD patients are included in the preliminary analyses with a mean age of 47. 8 had PBE >200 cells/μL at baseline, while 2 did not. The median number therapies used was 4 (IQR=0.75). All received glucocorticoids followed by an anti-TNF. There was no difference in the occurrence of hospitalization or surgery between the two cohorts. Overall 75% (n=6/8) participants with high PBE had clinical response to glucocorticoid exposure, seen as a 3-point decrease in HBI compared to 0% (n=0/2, p=0.5) in the low PBE cohort. With subsequent anti-TNF exposure, PBE rebounded in 6 participants. More patients in the high PBE group required anti-TNF dose escalation versus the low PBE group (63%, n=5/8 versus 50%, n=1/2, p=0.99). The proportion of patients with anti-TNF discontinuation was similar in both groups (high PBE, 50%, n=4/8 versus low PBE, 50%, n=1/2, p=1.00).ConclusionsPeripheral eosinophilia is seen in varying degrees in CD patients. Participants with high PBE appear to be more steroid-responsive which is typical for Th2-mediated pathways. They were less responsive to Th1-targeting anti-TNF therapies, requiring more dose-escalation and discontinued anti-TNF treatment. Completion of this study will help clarify the association between PBE in CD and treatment response.Funding AgenciesNone

P531 Stringent screening strategy significantly reduces reactivation rate of Tuberculosis in Patients with Inflammatory Bowel Disease on anti-TNF therapy in a TB endemic region

Abstract Background Anti-tumour necrosis factor (anti-TNF) therapy use in patients with inflammatory bowel disease (IBD) leads to increased risk of tuberculosis (TB) reactivation despite LTB screening, especially in TB endemic regions. We evaluated the effect of stringent screening strategy and latent tuberculosis (LTB) prophylaxis on TB reactivation. Methods We performed an ambispective comparison between patients who were started on anti-TNF therapy after January 2019 (Cohort A) and between Jan 2005-Dec 2018 (Cohort B). Cohort A patients were subjected to stringent screening criteria which included all: history of past TB/recent contact with active TB, CT (computed tomography) chest, IGRA (interferon-gamma release assay), TST (tuberculin skin test), and if any positive were given chemoprophylaxis. A cohort comparison was done to evaluate for risk reduction of TB following the stringent screening strategy. Results One hundred seventy-one patients (63-Ulcerative colitis/108-Crohn’s disease; mean age diagnosis-28.5±13.4 years; 60% males; median follow-up duration after anti-TNF:33months [interquartile range, 23–57 months]) were included. Among 112 in Cohort B 22(19.6%) had LTB and 19(17%) developed TB. In comparison, 26(44%) had LTB and only 1(1.7%) developed TB in Cohort A (p&amp;lt;0.01). On survival analysis, patients in Cohort B had a higher probability of TB reactivation compared to Cohort A at 5 years of follow up, HR-14.39 (95% CI,1.88- 109.81[p=0.010]) after adjusting for gender, age at anti-TNF therapy initiation, concomitant immunosuppression, the total number of anti-TNF doses and therapy escalation. *Log rank p value=0.006 Figure 1: Kaplan Meier curve analysis for probability of remaining free from tuberculosis between patients who were started on anti- TNF therapy till January 2019 (Cohort B) and those who were started on anti-TNF after January 2019 (Cohort A). *Log rank p value=0.02 Figure 2: Kaplan Meier curve analysis for probability of remaining free from tuberculosis between patients who had incomplete latent TB screening and those with complete TB screening. Conclusion The high risk of TB reactivation with anti-TNF therapy in TB endemic regions can be significantly mitigated with stringent LTB screening and chemoprophylaxis.

Clinical and Immunological Factors Associated with Recommended Trough Levels of Adalimumab and Infliximab in Patients with Crohn's Disease.

Introduction: Up to 40% of patients with Crohn’s disease do not respond to treatment with anti-TNF or lose response after the initial benefit. Low drug concentrations have been proposed as the main predictor of treatment failure. Our aim was to study the immunological profile and clinical evolution of patients with Crohn’s disease according to the anti-TNF dose and serum trough levels. Methods: Crohn’s disease patients in remission treated with infliximab or adalimumab at stable doses for at least for 3 months were included. Serum levels of anti-TNF, TNF-α, interferon-γ, and interleukin IL-12, IL-10, and IL-26 were determined in blood samples taken just before drug administration. Patients were classified according to anti-TNF levels below, within, or above the target level range and the use of intensified doses. Clinical evolution at 6 months was analyzed. Results: A total of 62 patients treated with infliximab (8 on intensified schedule) and 49 treated with adalimumab (7 on intensified schedule) were included. All infliximab-treated patients showed levels within the recommended range, but half of adalimumab-treated patients were below the recommended range. A significant negative relationship between body weight and adalimumab levels was observed, especially in patients treated with intensified doses. Patients with infliximab levels over 8 µg/ml presented higher median IL-10 than patients with in-range levels (84.0 pg/ml, interquartile range [IQR] 77.0–84.8 vs. 26.2 pg/mL, IQR 22.6–38.0; p < 0.001), along with lower values of interferon-γ (312.9 pg/ml, IQR 282.7–350.4 vs. 405.6 pg/ml, IQR 352.2–526.6; p = 0.005). Patients receiving intensified versus non-intensified doses of infliximab showed significantly higher IL-26 levels (91.8 pg/ml, IQR 75.6–109.5 vs. 20.5 pg/ml, IQR 16.2–32.2; p = 0.012), irrespective of serum drug levels. Patients with in-range levels of adalimumab showed higher values of IL-10 than patients with below-range levels (43.3 pg/ml, IQR 35.3–54.0 vs. 26.3 pg/ml, IQR 21.6–33.2; p = 0.001). Patients treated with intensified vs regular doses of adalimumab had increased levels of IL-12 (612.3 pg/ml, IQR 570.2–1353.7 vs. 516.4 pg/mL, IQR 474.5–591.2; p = 0.023). Four patients with low adalimumab levels (19%) and four treated with intensified doses were admitted to a hospital during a follow-up compared to none of the patients with levels within the range. Conclusion: Patients with Crohn’s disease treated with infliximab and adalimumab exhibit differences in serum levels of cytokines depending on the drug, dose intensification, and steady state trough serum levels.

Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn's disease.

Introduction:Anti-tumor necrosis factor (TNF) dose intensification represents an effective method of overcoming secondary loss of response (LOR); however, a subset of patients may not respond (tertiary non-response), or fail to demonstrate durable response (tertiary LOR) to intensified dosing. This systematic review and meta-analysis aimed to evaluate these outcomes to determine the clinical effectiveness of empiric dose intensification in Crohn’s disease.Methods:Multiple databases including MEDLINE and EMBASE were interrogated to identify studies that reported outcomes following anti-TNF dose intensification to address secondary LOR in Crohn’s disease. Studies that used anti-TNF levels as the primary basis for dose intensification were excluded. Studies that reported (1) tertiary response and tertiary non-response within 6 months or (2) tertiary response and tertiary LOR beyond 6 months, were pooled using a random effects model with risk ratio (RR) derived, quantifying the effect of each comparison.Results:Twenty-six studies reported outcomes following anti-TNF dose intensification to address secondary LOR. Short-term response within 12 weeks of any dose-intensification strategy was 33–90%, while sustained response (⩾48 weeks) was achieved in 25–85%. Tertiary non-response occurred in up to 45% of intensified patients within 6 months of anti-TNF dose intensification, while tertiary LOR beyond 6 months occurred in up to 64% of patients. Tertiary response was more likely than tertiary non-response within 6 months (RR 2.58, 95% CI (1.76, 3.79), I2 = 82%, 12 studies), while sustained response beyond 6 months compared to tertiary LOR (RR 1.10 (0.75, 1.61) I2 = 85%, 7 studies) was less convincing.Conclusion:Although anti-TNF dose intensification is clinically effective in patients with Crohn’s disease, particularly within the first 6 months, a proportion of patients will fail to demonstrate short-term and/or sustained clinical response. Hence, clinical reassessment following anti-TNF dose intensification, particularly beyond 6 months, remains important to differentiate between effective and ineffective dose-intensification strategies.

Combined Endoscopic and Radiologic Healing Is Associated With a Better Prognosis Than Endoscopic Healing Only in Patients With Crohn's Disease Receiving Anti-TNF Therapy.

INTRODUCTION:Although endoscopic healing (EH) is recommended as the therapeutic goal in patients with Crohn's disease (CD), combined EH and radiologic healing (RH) could be a more ideal therapeutic goal considering the transmural nature of CD. We compared the prognosis of patients with CD who achieved EH, RH, both EH and RH (deep healing; DH), or no healing under treatment with anti-tumor necrosis factor (TNF) agents.METHODS:We analyzed 392 patients with CD who received anti-TNF treatment for more than 1 year and evaluated with CT enterography or magnetic resonance enterography together with colonoscopy within 3 months between July 2017 and December 2018. Major outcomes (anti-TNF dose intensification, switch to other biologics, CD-related bowel resection, and hospitalization) were compared according to the EH and RH status.RESULTS:During the follow-up (median 18 months; interquartile range, 15–21), the DH group showed a better rate of major outcome-free survival compared with other groups (P < 0.001). In multivariable analysis, elevated C-reactive protein (adjusted hazard ratio [aHR], 2.166; 95% confidence interval [CI], 1.508–3.110; P < 0.001), EH-only (aHR, 3.903; 95% CI, 1.635–9.315; P = 0.002), RH-only (aHR, 3.843; 95% CI, 1.545–9.558; P = 0.004), and no healing (aHR, 8.844; 95% CI, 4.268–18.323; P < 0.001) were associated with increased risks of major outcomes.DISCUSSION:Patients with CD who achieved DH under anti-TNF therapy showed a better prognosis compared with those who only achieved EH. The possibility of DH being used as a new therapeutic target for patients with CD should be investigated in further studies.

Real-World Incidence of Suboptimal Response to Anti-Tumor Necrosis Factor Therapy for Ulcerative Colitis: A Nationwide Population-Based Study.

Background/AimsAlthough anti-tumor necrosis factor (TNF) agents have been widely used to treat ulcerative colitis (UC), the real-world incidence of suboptimal response to anti-TNF agents has not been thoroughly investigated, especially among Asians.MethodsUsing the Korean National Health Insurance database, we collected data on UC patients who initiated anti-TNF agents between July 1, 2014, and June 30, 2017. We assessed suboptimal responses, including anti-TNF discontinuation or dose escalation, switching to other biologics, augmentation with a non-biologic therapy, and the requirement for colectomy.ResultsA total of 1,268 patients were included as new anti-TNF users (infliximab 713, adalimumab 433, golimumab 122). The proportion of patients who experienced at least one suboptimal response within 1 year among all patients was 63.5%, including 59.1%, 69.5%, and 68.0% of patients treated with infliximab, adalimumab, and golimumab, respectively. The cumulative incidences of at least one suboptimal response over time were 41.5%, 63.7%, 80.5%, and 87.1% at 6, 12, 24, and 36 months, respectively. Cox proportional hazards modeling revealed that adalimumab was associated with a higher risk of at least one suboptimal response (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.13 to 1.48), dose escalation (HR, 4.35; 95% CI, 2.97 to 6.38) and discontinuation (HR, 1.25; 95% CI, 1.03 to 1.52) than infliximab. Golimumab was associated with a higher risk of switching to other biologics than infliximab (HR, 1.78; 95% CI, 1.21 to 2.60).ConclusionsMore than half of Korean UC patients had suboptimal responses to anti-TNF agents within 1 year. UC patients treated with infliximab might be less prone to suboptimal responses than those treated with adalimumab or golimumab.

Anti-TNF dose can be reduced in PsA and axSpA.

Anti-TNF dose can be reduced in PsA and axSpA.

P277 Frequency and effectiveness of empirical anti-TNF dose intensification in Inflammatory Bowel Disease: systematic review with meta-analysis

Abstract Background Loss of response to anti-TNF (tumor necrosis factor) therapies in inflammatory bowel disease occurs in a high proportion of patients. However, the precise incidence of dose intensification (DI) and its effectiveness remains unclear. Our aims were: 1) To evaluate the need of DI of anti-TNF therapy either by increasing the dose or decreasing doses’ interval; 2) To evaluate possible variables influencing its requirement; 3) To assess the effectiveness of empirical DI. Methods Bibliographical searches were performed in Pubmed, Embase, the Cochrane Library and CINAHL. Selection: prospective and retrospective studies assessing loss of response to anti-TNF therapy, considered as the need of DI, in Crohn’s disease (CD) and ulcerative colitis (UC) patients treated for at least 12 weeks with an anti-TNF drug [infliximab (IFX), adalimumab (ADA), certolizumab or golimumab]. Exclusion criteria: studies using anti-TNF as prophylaxis for postoperative recurrence in CD or those where DI was based on therapeutic drug monitoring. Data synthesis: Effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (UC vs. CD), anti-TNF drug and follow-up. Subgroup analyses were performed to explore heterogeneity. Results In total, 174 studies (32,031 patients) were included. The overall rate of DI requirement after 12 months follow-up was 27% (95%CI 23-31, I2=96%, 51 studies) in naïve patients and 38% (95%CI 31-46, I2=87%, 18 studies) in non-naïve patients. The rate of DI requirement was higher in patients with prior anti-TNF exposure (c²=6.5, P=0.01) and in UC patients (c²=4.7, P=0.03). The rate of DI requirement in naïve patients after 36 months follow-up was 35% (95%CI 27-43%; I2=98%; 22 studies). The overall short-term response and remission rates to empirical DI in naïve patients were 66% (95%CI 61-71%; I2=81%; 35 studies) and 48% (95%CI 35-62%; I2=97%; 27 studies), respectively. Subgroup analyses are presented in the tables. Conclusion Loss of response to anti-TNF agents ―and consequent DI― occur frequently in IBD (approximately in 1/4 at one year and in 1/3 at 3 years). DI requirement is higher in UC patients and in those with prior anti-TNF exposure. Empirical DI is a relatively effective therapeutic option.

Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis.

Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. Selection: prospective and retrospective studies assessing DI in Crohn’s disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn’s disease or those where DI was based on therapeutic drug monitoring. Data synthesis: effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn’s disease), anti-TNF drug and follow-up. Results: One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24–32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31–47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28–43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48–78%; I2 = 99%; 32 studies) and 48% (95% CI: 39–58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents―and, consequently, DI―occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

BackgroundNew medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients.MethodsWe investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy.ResultsDasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy.ConclusionOur findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

De-escalation from Dose-Intensified Anti-TNF Therapy Is Successful in the Majority of IBD Patients at 12Months.

Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate. To evaluate rates of successful de-escalation at 12months and to determine factors that may predict success. Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly. Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12months post-de-escalation. Median time to failure was 6months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6months (3.1 vs. 4.6, p = 0.95) and 12months (3.2 vs. 4.5, p = 0.58) post-de-escalation. Nearly two-thirds of patients remained on reduced anti-TNF dosing 12months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.