anti-TNF Discontinuation Research Articles

P558 Should we introduce early a new biological agent in patients with Inflammatory Bowel Disease after anti-TNF discontinuation due to severe anti-TNF-induced skin lesions? A multicenter cohort study

Abstract Background Data to manage patients with Inflammatory Bowel Disease (IBD) after anti-TNF discontinuation due to severe induced skin lesions are scarce. Our study aimed to assess dermatological and IBD outcomes after discontinuation of an anti-TNF agent related to skin side effects. Methods We conducted a multicenter retrospective study including consecutive IBD patients who discontinued anti-TNF due to induced skin lesions. Objectives were to determine factors associated with remission of induced skin lesions and with IBD relapse in patients with inactive disease at inclusion, particularly the impact of early introduction of a new biological agent within three months of anti-TNF discontinuation. Results Among the 181 patients (134 women, 160 Crohn’s disease) included in the 13 participating centers, 99 (55%) started a new biological agent within the first three months that was mainly ustekinumab in 75% of them. Remission of induced skin lesions occurred in 110 (62%) patients with a median [interquartile range (IQR)] interval of 8.0 (6.8–11.0) months since anti-TNF discontinuation. Scalp location was independently associated with a reduced risk of remission of induced skin lesions [HR 0.64 (95%CI 0.43- 0.94), p=0.02] while early biological therapy was independently associated with a higher probability of remission of skin lesions [HR 1.64 (95%CI 1.1–2.5), p=0.02]. Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 (51%) patients with a median (IQR) interval of 26.0(23.0–39.1) months. Survival rates without IBD relapse at 1 year were 85.8% (95%CI 77.5–94.9) in the early introduction group and 59.3% (95%CI 48.9–71.9) in the other group (p<0.01). Conclusion Early introduction of a new biological is associated with higher probability of healing of anti-TNF-induced skin lesions and significantly reduces risk of IBD relapse.

P619 Patterns of Anti-TNF Prescribing & Therapy Outcome in a Large Multicentre Cohort of Inflammatory Bowel Disease Patients

Abstract Background Anti-TNF agents are effective therapies for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients lose response over time. Real world data on prescribing practices and outcome of anti-TNF therapy are of utility to practicing clinicians Methods To evaluate Anti-TNF prescribing practice and durability of Anti-TNF response in a large multicentre IBD cohort. IBD patients commencing an anti-TNF agent, as first biologic therapy, at participating academic centres were identified from institutional databases. Baseline demographic data, concomitant medication and biologic therapy history were collected. Adalimumab(ADA) and Golimumab(GOL) were consider subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of first and second line anti-TNF therapy was documented. Kaplan-Meier survival curves were constructed for time based analyses. P values less than 0.05 were considered significant in all analyses. Results N=991 patients with IBD were included in the study. 29%, 69% and 2% had UC, CD and IBD-U respectively; median [IQR] age 27 [19–37] years; 50% female. 31%, 63% and 4% received infliximab(IFX), ADA and GOL respectively as first-line anti-TNF therapy. 35% of patients received an immunomodulator in combination with first-line anti-TNF agent. Median [95% CI] survival free of therapy discontinuation for first and second-line anti-TNF agents was 4.6 [3.7 – 5.3] years and 3.0 [2.1 – 3.9] years respectively. Survival free of anti-TNF discontinuation was significantly shorter for IFX monotherapy group compared with IFX combination therapy, SC anti-TNF monotherapy and SC anti-TNF combination therapy groups, p=0.005. Conclusion While anti-TNF therapies are effective a significant proportion of patients discontinue therapy over time. Second line anti-TNF therapy results in a less durable response with a shorter time to drug discontinuation compared with first line anti-TNF therapy. The use of a combination immunomodulator is particularly important with infliximab therapy, however, does not influence durability of response for subcutaneous anti-TNF agents.

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.

P207 Clinical outcome of patients with Ulcerative colitis after anti-TNF discontinuation -\t10 years follow up

Abstract Background Biological therapy for ulcerative colitis (UC) such as anti-TNF have shown high efficacy in achieving remission. There is a lack of information about the long-term outcomes after biologic withdrawal and validated clinical, immunologic, genetic or laboratory markers that can predict outcome after withdrawal accurately. The aims of this study were to describe the long-term outcomes after anti-TNF withdrawal and discover potential biomarkers to predict long-term remission as an approach to towards personalized medicine. Methods 75 patients with moderate to severe UC treated to remission with anti-TNF were included in the study. These patients were categorized as either “Long term remission” (LTR) or “Relapse”. The “Relapse” group were divided in subgroups by the highest treatment level needed to obtain remission the last 3 years of observation: non-biological therapy, biological therapy or colectomy. LTR were divided in LTR + immunomodulating (imids) drugs and a new clinical phenotype “Near the Cure of disease” (NCD), defined as > 3 years in remission with no medication or 5ASA only. Results The median (IQR) observation time of all patients included were 121(111–137) months. Of the 75 patients 46 (61%) did not receive biological therapy including 23 (31%) in LTR + imids. Of the 23 patients 16 were defined as NCD with an observation time of median (IQR) 95(77–113) months. Fourteen patients underwent colectomy and 15 patients received biological therapy the last 3 years of the follow-up. Mucosal TNF copies/µg mRNA < 10 000 at anti-TNF discontinuation predicted long-term remission, biological free remission and lower risk of colectomy with a HR 0.36 (0.14–0.92) for long term remission, HR 0.17 (0.04–0.78) for biological free remission and HR 0.12 (0.01–0.91) for coelctomy. Conclusion This 10-year anti-TNF discontinuation follow up study of UC shows that 61% of patients experience an altered phenotype to a milder disease course without need of biological therapy. Normalized mucosal TNF transcript predict this mild disease course and lower risk of colectomy. Of special interest is that 21% of the patients defined as “Near the cure of disease” were in long-term remission without any medication or receiving 5ASA only.

DOP75 Loss-of-response and immunogenicity following immunomodulator withdrawal from anti-tumour necrosis factor alpha combination therapy: Results from a large retrospective cohort study

Abstract Background Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels. Methods This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated >4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for >30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure. Results We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal. Conclusion Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.

AB0563 DISCONTINUATION OF ANTI-TNFα IN PATIENTS WITH PSORIATIC ARTHRITIS: A SINGLE-CENTER EXPERIENCE

Background:TNF inhibitors have been largely demonstrated to be effective and reasonably safe for the treatment of psoriatic arthritis (PsA). Current EULAR guidelines recommend the use of an anti-TNF as first choice treatment in patients with PsA for whom a synthetic DMARD (usually methotrexate or leflunomide) is not efficacious or not well tolerated [1]. In a scenario where biologic treatments are easily available, and the treat to target strategy is widely accepted, a complete disease remission or at least a minimal disease activity are considered realistic goals to be achieved in a growing proportion of patients [2]. However, there remains very little research regarding anti-TNF discontinuation in patients who achieved a complete remission [3-5].Objectives:The primary aim of this study was to measure the disease-free interval after anti-TNF discontinuation, secondary it was investigated whether the use of Power Doppler Ultrasound (PDUS) and Contrast Enhanced Ultrasound (CEUS) could improve the diagnostic accuracy in the recognition of the relapse. Finally, we wanted to characterize the clinical features of the disease recurrence.Methods:From June 2018, 35 patients with PsA (27 males and 8 female) treated with anti-TNF, in stable remission were prospectively monitored for 1 year after treatment discontinuation. Remission was defined as documented absence of clinical and ultrasonographic signs of arthritis or enthesitis. Complete rheumatological and dermatological examinations were performed in all participants, at baseline and every 8-12 weeks: American College of Rheumatology (ACR) 66-68 joint count; Psoriasis Area Severity Index (PASI); patient pain visual analog score (VAS); patient global disease activity VAS; Health Assessment Questionnaire (HAQ); Leeds Enthesitis Index (LEI); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Bath Ankylosing Spondylitis Functional Index (BASFI); Power Doppler Ultrasound (PDUS) of the involved joints and entheses, Contrast Enhanced Ultrasound (CEUS) of a selected joint or enthesis and laboratory inflammation tests.Results:31 out of the 35 enrolled patients, experienced a disease recurrence with an average disease-free interval of 27.9±21.1 weeks (Figure 1). In 3 patients the treatment was restored for a relapse of the skin psoriasis, 8 patients reported only axial symptoms of disease relapse and 20 patients had both axial and peripheral joints involvement (average DAPSA score of 23.6±11.1; average BASDAI score of 4.7±2.6; average BASFI score 4.5±2.9). In all cases the disease flare was moderate and all patients promptly regained remission after restarting the treatment. Both PDUS and CEUS were safe and reliable showing a good percentage of accordance (95,4%) in detecting synovitis and enthesitis.Conclusion:The rate of disease relapse of PsA after anti-TNF discontinuation is relevant. However the disease-free interval was not short. Retreatment with the same anti-TNF was effective and safe.

Selecting the Ideal Candidate for Anti-TNF Discontinuation in Crohn’s Disease, Dream or Reality?

Selecting the Ideal Candidate for Anti-TNF Discontinuation in Crohn’s Disease, Dream or Reality?

Clinical outcome after anti-tumour necrosis factor therapy discontinuation in 1000 patients with inflammatory bowel disease: the EVODIS long-term study.

The long-term outcome of patients after antitumour necrosis factor alpha (anti-TNF) discontinuation is not well known. To assess the risk of relapse in the long-term after anti-TNF discontinuation. This was an extension of the evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti-TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey-Bradshaw index ≤4 points in Crohn's disease, a partial Mayo score ≤2 in ulcerative colitis and the absence of fistula drainage despite gentle finger compression in perianal disease. This was an observational, retrospective, multicenter study. A total of 1055 patients were included. The median follow-up time was 34months. The incidence rate of relapse was 12% per patient-year (95% confidence interval [CI]=11-14). The cumulative incidence of relapse was 50% (95% CI=47-53): 19% at one year, 31% at 2years, 38% at 3years, 44% at 4years and 48% at 5years of follow-up. Of the 60% patients retreated with the same anti-TNF after relapse, 73% regained remission. Of the 75 patients who did not respond, 48% achieved remission with other therapies. Of the 190 patients who started other therapies after relapse, 62% achieved remission with the new treatment. A significant proportion of patients who discontinued the anti-TNF remained in remission. In case of relapse, retreatment with the same anti-TNF was usually effective. Approximately half of the patients who did not respond after retreatment achieved remission with other therapies.

Anti-Tnf Side Effects in the Treatment of Chronic Inflammatory Bowel Disease

IBD is a common, serious and disabling chronic digestive disease, Their different manifestations, whether digestive and extra-digestive, require a multi-professional care adapted to each specific patient. Anti-TNFs are now an essential therapeutic weapon in the management of inflammatory bowel disease (IBD). Their effectiveness in both the short and long term has been demonstrated in various studies. However short and long term anti-tnf results vary from patient to patient which can be explained in many cases by the significant number of discontinued treatment in patients that experience side effects. The purpose of our work is to study the different side effects occurring in patients under biotherapy, the management of these side effects and their prevention. We prospectively analyzed since four years the medical records of 54 IBD patients who received anti-TNF treatment. An exhaustive pre-therapeutic assessment was performed systematically in all patients. A clinical and biological control was carried out systematically before each therapeutic administration to search for undesirable reactions. Side effects were classified into several categories including immediate hypersensitivity reactions, dermatological complications, infectious, neurological, haematological, neoplasic and cardiac complications. During this period, 54 patients were treated with biotherapies, representing 24.2% of all IBD patients. We observed 29 side effects, an incidence of 46% including two severe effects 3.5%, occurring on average after one month of treatment. The hematological undesirable effects were the most frequent appeared in 14 patients (26%), severe infection specifically tuberculosis appeared in 2 patients (3.6%), allergic effects were severe in only one case (anaphylactic shock), finally the secondary cutaneous lesions of Anti-TNF were observed in a single patient (extensive psoriasis). Severe adverse reactions led to permanent discontinuation of Anti-TNF in 24.1% of cases. The use of anti-TNF treatment is likely to generate numerous undesirable effects, hence the advantage of respecting the recommendations relating to the assessment before any treatment with biotherapy and of making regular clinical follow-up during treatment with a meticulous clinical examination as well as biological monitoring in order to prevent the occurrence of these complications, and to manage them correctly once they appear.

Anti-Tnf Side Effects in the Treatment of Chronic Inflammatory Bowel Disease

IBD is a common, serious and disabling chronic digestive disease, Their different manifestations, whether digestive and extra-digestive, require a multi-professional care adapted to each specific patient. Anti-TNFs are now an essential therapeutic weapon in the management of inflammatory bowel disease (IBD). Their effectiveness in both the short and long term has been demonstrated in various studies. However short and long term anti-tnf results vary from patient to patient which can be explained in many cases by the significant number of discontinued treatment in patients that experience side effects. The purpose of our work is to study the different side effects occurring in patients under biotherapy, the management of these side effects and their prevention. We prospectively analyzed since four years the medical records of 54 IBD patients who received anti-TNF treatment. An exhaustive pre-therapeutic assessment was performed systematically in all patients. A clinical and biological control was carried out systematically before each therapeutic administration to search for undesirable reactions. Side effects were classified into several categories including immediate hypersensitivity reactions, dermatological complications, infectious, neurological, haematological, neoplasic and cardiac complications. During this period, 54 patients were treated with biotherapies, representing 24.2% of all IBD patients. We observed 29 side effects, an incidence of 46% including two severe effects 3.5%, occurring on average after one month of treatment. The hematological undesirable effects were the most frequent appeared in 14 patients (26%), severe infection specifically tuberculosis appeared in 2 patients (3.6%), allergic effects were severe in only one case (anaphylactic shock), finally the secondary cutaneous lesions of Anti-TNF were observed in a single patient (extensive psoriasis). Severe adverse reactions led to permanent discontinuation of Anti-TNF in 24.1% of cases. The use of anti-TNF treatment is likely to generate numerous undesirable effects, hence the advantage of respecting the recommendations relating to the assessment before any treatment with biotherapy and of making regular clinical follow-up during treatment with a meticulous clinical examination as well as biological monitoring in order to prevent the occurrence of these complications, and to manage them correctly once they appear.

P020 Incidence of Suboptimal Response to First-Line Anti-TNF Therapy in Patients with IBD in Argentina: Results from the EXPLORE Study.

BACKGROUND: While anti-TNFs have long been a mainstay in UC and CD management, a considerable proportion of patients experience treatment failure. The aim of this sub-analysis from the main EXPLORE study (NCT03090139) was to assess suboptimal response to anti-TNFs in Argentina. METHODS: Patients with Ulcerative Colitis (UC) and Crohn´s Disease (CD) who initiated first-line anti-TNF therapy between March 2010 and March 2015 from 5 centers in Argentina were enrolled. Anti-TNF dose escalation or discontinuation, IBD-related surgery or hospitalizations, and augmentation of non-biological therapy were considered indicators of suboptimal response to anti-TNF therapy. Primary non-response (PNR) was defined as suboptimal response that occurred within 4 months of anti-TNF initiation (index date), and secondary loss of response (SLOR) if this occurred > 4 months after initiation. The cumulative incidence (CI) of suboptimal response to first-line anti-TNF therapy was evaluated within 2 years after treatment initiation. RESULTS: A total of 78 first-line anti-TNF treated patients were analyzed (n = 40 CD, n = 38 UC). Females represented 45.0% and 52.6% in CD and UC, respectively. At diagnosis, over half of the CD patients had ileocolonic disease involvement (55.0%), while 47.4% and 39.5% of the UC patients showed a left-sided colitis and extensive involvement (including pancolitis), respectively. Median age at diagnosis was 31 years (range 13-67) and 29 years (range 11-80) for CD and UC, respectively. Median age at first-line anti-TNF treatment was 34.5 years (range 22-70 for CD and 19-81 for UC). About 36.9% of CD patients had a disease duration between 0 to < 2 years to index date, 33.3% ≥ 2 to 5 years, 10.3% ≥ 5 to < 8 years and 20.5% ≥ 8 years; the respective proportions were 50.0%, 15.8%, 13.2% and 21.0% in UC.Within 2 years of treatment initiation, PNR was 15.0% in CD (n = 6) and 10.5% in UC (n = 4), while SLOR was 42.5% in CD (n = 17) and 31.6% in UC (n = 12). The CI of suboptimal response for the first anti-TNF agent was 37.9% and 30.0% at 12 months and 49.2% and 44.5% at 24 months for CD and UC, respectively. Augmentation in non-biological therapy and dose escalation of the anti-TNF were the most frequent indicators of suboptimal response in both conditions (30.4% and 26.1% [CD]; 25.0% and 56.3% [UC]). CONCLUSION: In accordance with other real-world studies, almost half of first-line anti-TNF treated IBD patients evaluated in 5 centers in Argentina experienced suboptimal response to their first-line anti-TNF therapy within 2 years. Determining response-predictive biomarkers and the use of newer therapies may help improve treatment outcomes in IBD.

Anxiety and Depression Leads to Anti–Tumor Necrosis Factor Discontinuation in Inflammatory Bowel Disease

Anxiety and mood disorders (AMDs) are common among persons with inflammatory bowel diseases (IBD) and are associated with increased health care use and lower quality of life. We assessed the effects of AMDs on persistence on anti-tumor necrosis factor (anti-TNF) therapy in patients with IBD, and risk of IBD-related adverse outcomes after therapy initiation. We identified all persons with IBD in Manitoba, Canada who were dispensed an anti-TNF agent from 2001 through 2016 and then identified those with a validated administrative definition of AMD in the 2 years before initiation of therapy. Survival analysis was used to assess the association between active AMDs and anti-TNF discontinuation and the first occurrence of an IBD-related adverse outcome (defined as IBD-related hospitalization or surgery, new or recurrent corticosteroid use, switching to an alternative anti-TNF, or death). We used Cox proportional hazards multivariable regression models to adjust for demographic and clinical factors associated with outcomes. We identified 1135 persons with IBD who began anti-TNF therapy; 178 of these patients (15.7%) met the diagnostic criteria for an AMD. AMDs significantly increased risk of discontinuation of anti-TNF therapy (adjusted hazard ratio, 1.28; 95% CI, 1.03-1.59) and discontinuation in the 1 year following anti-TNF initiation (hazard ratio, 1.50; 95% CI, 1.15-1.94). There was no association between AMDs and subsequent risk of IBD-related adverse events. Patients with IBD and an AMD within 2 years before starting anti-TNF therapy are at increased risk of discontinuing therapy, compared to patients with IBD without AMD. Studies are needed to determine if treatment of AMDs increases compliance with treatment.

Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: The EXPLORE study

BackgroundIncidence of inflammatory bowel disease (IBD) is increasing in newly industrialised countries (NICs); however, data on suboptimal response to anti-tumor necrosis factor (anti-TNF) agents are limited. ObjectivesTo assess incidence and indicators of suboptimal response to first anti-TNF therapy in IBD patients in NICs. MethodsA chart review was conducted in ten countries from Asia-Pacific (APAC), Latin America (LatAm), and Russia and the Middle East (RME) regions among patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD), initiating anti-TNF therapy in 2010–2015. The cumulative incidence of suboptimal response to anti-TNF therapy was assessed using the following indicators: dose escalation or discontinuation, augmentation with non-biologic therapy, IBD-related hospitalization, or surgery. ResultsThe study included 1,674 patients (570 UC; 1,104 CD). At 24 months, 32.9% of UC (APAC: 45.1%; LatAm: 38.2%; RME: 23.8%) and 41.2% of CD patients (APAC: 54.1%; LatAm: 42.5%; RME: 29.5%) had experienced suboptimal response. The most frequent first indicator was non-biologic therapy augmentation in LatAm (41.7%), IBD-related hospitalization in RME (UC: 50.7%; CD:37.3%) and in APAC for CD (39.1%), and anti-TNF discontinuation in APAC for UC (38.3%). ConclusionSuboptimal response to anti-TNF agents is common in IBD patients in NICs. Observed regional differences in the incidence and indicators may reflect local practice and anti-TNF restrictions in IBD management. NCT Registration NumberNCT03090139.

Articular manifestations in patients with inflammatory bowel disease treated with vedolizumab.

Vedolizumab (VDZ) has been incriminated in the occurrence of articular manifestations in patients with inflammatory bowel diseases (IBDs). The aim of this study was to describe musculoskeletal manifestations occurring in IBD patients treated by VDZ and to identify risk factors. In this retrospective monocentric study, we included all consecutive patients treated by VDZ for IBD in our hospital. Incident musculoskeletal manifestations occurring during VDZ treatment were analysed and characteristics of patients with and without articular inflammatory manifestations were compared. Between 2013 and 2017, 112 patients were treated with VDZ for IBD: ulcerative colitis (n = 59), Crohn's disease (n = 49) and undetermined colitis (n = 4). Four patients (3.6%) had a history of SpA, whereas 13 (11.6%) had a history of peripheral arthralgia. Some 102 (91.1%) patients had previously received anti-TNF. After a mean (S.d.) follow-up of 11.4 (8.6) months, 32 (28.6%) patients presented 35 musculoskeletal manifestations, of which 18 were mechanical and 17 inflammatory. Among the latter, 11 had axial or peripheral SpA, 5 had early reversible arthralgia and 1 had chondrocalcinosis (n = 1). Among the 11 SpA patients, only 3 (2.6%) had inactive IBD and may be considered as paradoxical SpA. The only factor associated with occurrence of inflammatory manifestations was history of inflammatory articular manifestation [7/16 (43.8%) vs 10/80 (12.5%), P = 0.007]. Musculoskeletal manifestations occurred in almost 30% of IBD patients treated with VDZ, but only half of them were inflammatory. Since most of the patients previously received anti-TNF, occurrence of inflammatory articular manifestations might rather be linked to anti-TNF discontinuation than to VDZ itself.

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

Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis

Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P= .035). Factors associated with lower ALP were normal ALP at baseline (P < .01), treatment with adalimumab (P= .090), and treatment in Europe (P= .083). In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.

P386 Long-term evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (IBD): A multicentre study

Abstract Background (1) To assess the risk of relapse at long-term after anti-TNF discontinuation, (2) to identify the factors associated with relapse, (3) to calculate the response rate to re-treatment with the same anti-TNF, (4) to evaluate the safety of re-treatment with these drugs, and (5) to investigate the rate of complications of patients that relapsed. Methods A retrospective, observational, multicentre study conducted at 39 Spanish centres. Crohn’s disease or ulcerative colitis patients who had been treated with anti-TNFs and in whom these drugs had been withdrawn after achieving clinical remission, were included. Follow-up time after anti-TNF discontinuation was at least 6 months. Results Six hundred and thirty-seven patients were included (53% women, mean age 42, 68% Crohn’s disease). The reasons for discontinuation were: 74% elective decision, 19% adverse events, and 7% remission after top-down strategy. The median follow-up time was 60 months. In patients who relapsed, the median time to relapse after anti-TNF discontinuation was 24 months. The cumulative incidence of relapse was 54% (50–58%): 17% at 1 year, 28% at 2, 34% at 3, and 45% at 5 years after anti-TNF withdrawal. The incidence rate of relapse was 11% per patient-year (10–12%). At the time of anti-TNF discontinuation, endoscopy was performed in 48% of patients; of these, 88% had a normal endoscopy and 9% had mild activity. 68% of patients maintained immunomodulators (IMMs) after discontinuing the anti-TNF. In the multivariate analysis, older age at diagnosis (HR = 0.99; 95% CI = 0.98–0.99, p = 0.003) and the maintenance of IMMs after anti-TNF discontinuation (HR = 0.53; 95% CI = 0.42–0.66, p &amp;lt; 0.0001) were associated with a lower risk of relapse. After relapse, 49% of patients were re-treated with the same anti-TNF, 47% received another drug, and 4% were operated on. Of patients who restarted the same anti-TNF, 79% (70–86%) achieved remission. After re-treatment, 11% presented adverse events, all mild. Of the 48 patients who did not respond after anti-TNF re-treatment, 41% (26–57%) achieved remission with other therapies, and 21% of these patients relapsed at the end of follow-up. Of the 161 patients who started other treatment after relapse, 62% (54–70%) achieved remission with the new treatment, and 30% of these patients relapsed. Conclusion The incidence rate of relapse after anti-TNF discontinuation in IBD Patients who were in remission was 11% per patient-year, and 45% relapsed at 5 years. Older age at diagnosis and maintenance treatment with IMMs were associated with a lower risk of relapse. Re-treatment of relapse with the same anti-TNF was effective and safe. Less than half of the patients who did not respond after re-treatment achieved remission with other therapies.

P625 Kinetics and outcomes of transmural healing in patients with Crohn’s disease treated with anti-TNF therapy

Abstract Background Transmural healing is a promising target in Crohns’ disease (CD) but remains poorly investigated. We aimed to evaluate the kinetics of transmural healing in CD treated with anti-TNF and to assess whether transmural healing is associated with more favourable outcomes. Methods It was a retrospective study from an MRI database of 449 patients performing MRI for luminal CD. Inclusion criteria were: CD patients older than 18 years-old receiving anti-TNF therapy, with an objective sign of inflammation on morphological evaluation (endoscopy or cross-sectional imaging), who underwent at least one MRI examination to assess therapeutic efficacy and follow-up longer than 6 months. Patients treated with anti-TNF agents for treat isolated perianal lesions were excluded. We used a statistical model based on imputation according to the last observation carry forward and clinical relevance. Each CD MRI lesions were then assessed every month during the first year. For segmental analysis, we used a division into six segments (jejunum, ileum, right colon, transverse colon, left/sigmoid colon and rectum). Transmural healing was defined as no MRI lesions. Results Overall, 148 patients were included. Among them, 81 were female (55.7%), 43 (34.4%) were current smokers and 56 (37.8%) had prior intestinal resection. The median CD duration at baseline was 7.6 years [1.4–15.2]. At baseline, 80 patients (54.4%) were anti-TNF-naïve. During the study, 69 patients (46.6%) were treated with infliximab, 77 patients (52%) received adalimumab while only 2 patients (1.4%) were treated with golimumab A combination therapy with thiopurines or methotrexate was found in 108 patients (74.0%) and 30 patients (20.3%) received concomitant steroids at the time of inclusion. Among 148 patients and 303 MRIs, 387 segments were analyzed. The rate of transmural healing was optimal between M6 and M8 and plateaued from the eighth month. The kinetics of transmural healing in CD patients treated with anti-TNF agents is presented in Figure 1. Among the 148 patients with CD, 29 patients underwent intestinal resection (19.6%), 32 patients (21.6%) required an hospitalisation due to CD and 61 patients (41.2%) discontinued anti-TNF for therapeutic failure. In multivariable analyses, transmural healing was associated with decreased risk of surgery (HR=0.19[0.04–0.86];p = 0.03) and anti-TNF discontinuation (HR=0.42 [0.21–0.84]; p = 0.01) while we observed a trend for decrease risk of CD-related hospitalisation (HR=0.56[0.22–1.43];p = 0.23). Conclusion Transmural healing, which is associated with better outcomes in CD, can be achieved in more than half of patients with CD. The best time to assess transmural healing was between 6 to 8 months after starting anti-TNF therapy.

P497 Is mucosal healing sufficient paramater for anti-TNF discontinuation?

Abstract Background Long-term treatment with biologic therapy alongside with immunomodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. Nowadays, there is not a clear recommendation for de-escalation of therapy in patients on biologic treatment. The aim of the study was to evaluate relapse rate in 4 ili 2 years follow-up in patients with mucosal healing after two years of anti-TNF treatment, regardless achieved histological remission. Methods 52 patients with IBD after two years treatment with anti-TNF agents (Infliksimab (IFX) and Adalimumab (ADA)) and achieved mucosal healing, were enrolled in this retrospective study. Mayo endoscopic sub-score (0,1) and SES (&amp;lt;2) was used to define mucosal healing in UC and CD patients, respectively. For the assessment of histological activity Nancy and Global Histologic Disease Activity Score (GHAS) were used. Histologic remission was defined by Nancy’s score ≤ 1 and GHAS ≤ 4. Data were collected for 4 years follow-up period after discontinuation of anti-TNF agents. Statistical analysis was carried out using SPSS 20.0 (Chicago, IL). Results From 52 patients 40.38% (21/52) patients had UC, and 59.61 % (31/52) had CD with an average disease duration of 11.57 (SD ± 6.28) years. Gender distribution was relatively equal, 46% men (24/52), with an average age of 40.66 (SD ± 11.15) years. All of the patients were on anti-TNF therapy and had mucosal healing at the moment of discontinuation, 55% (29/52) were on IFX, 35% (23/52) were on ADA, respectively. 48.07% (25/52), were with pathohistological remission of disease. In 4 years follow-up after anti-TNF therapy discontinuation, 59.61% (31/52) relapsed, with an estimated period of relapse time of 15.4 (SD ± 9.83) months. Using Spearman`s correlation moderate relation was revealed between histological activity and relapse (rho 0.467, p &amp;lt; 0.001). Probability of relapse within 4 years in this group of patients with histologically active disease was higher (p &amp;lt; 0.01, OR 2.72, 95% Cl 1.24–5.92). Conclusion Achieving both, endoscopic and histological remission, may be a good parameter in making a decision when to de-escalate anti-TNF therapy.

P556 Long-term probability of retreatment with anti-TNF therapy after discontinuation based on mucosal healing in inflammatory bowel disease

Abstract Background To evaluate the need for retreatment with anti-TNF due to relapse after discontinuation based on mucosal healing in inflammatory bowel disease (IBD), as well as the influencing factors and the response to reintroduction. Methods Descriptive retrospective study of IBD patients in whom anti-TNF treatment was discontinued after mucosal healing had been proved, between June 2009 and May 2016. Demographic and phenotypic characteristics, biologic and immunomodulator (IM) therapy history, laboratory markers and histopathologic evaluation were noted. We evaluated the relapse rate after discontinuation of anti-TNF, as well as the need for reintroduction and its success rate. Results We included 100 patients, 69 of them affected by Crohn’s disease (CD), 29 with ulcerative colitis (UC) and 2 unclassified colitis. From those with CD, inflammatory behaviour (62%) and ileocolonic localisation (53%) were the most frequent conditions. Seventy-four per cent of UC patients had pancolonic involvement. Biological therapy had been indicated because of corticodependence in 66% (vs. 32% corticorefractoriness). The anti-TNF drug was infiliximab in 60 patients, adalimumab in 38, 1 certolizumab and one had been treated with golimumab. Endoscopic biopsies showed quiescent disease in 63 of 83 patients. Eighty-three per cent of patients were treated with IM after removal of anti-TNF. After a mean follow-up of 57 months, 63 patients relapsed, 52 of them needing anti-TNF reintroduction. Reintroduction rates at 12, 36 and 60 months were 19.5%, 43.5% and 52% respectively with a response after the re-treatment of 76,6%. Univariant analysis showed a higher risk in CD (61 vs. 31%, p = 0.008). Within the CD patients, the risk of reintroduction was lower in A3 (30 vs. 66%, p = 0.03) and B2 (31 vs. 69%, p = 0.006) patterns, and higher if the indication had been corticodependence (68% vs. 37%, p = 0.02). Multivariant analysis confirms the protective effect of B2 behaviour and worse outcomes for corticodependence antecedent. Considering UC, the retreatment probability was superior for those patients without IM therapy after anti-TNF discontinuation (57 vs. 22%), although this association did not reach statistical significance (p = 0.08). Conclusion The risk of needing reintroduction of anti-TNF therapy after mucosal healing in IBD is around 50% in 5 years, being superior in CD patients. Reintroduction success rate is 76%. In CD, this risk is higher when the reason for starting anti-TNF was corticodependence, and much lower when stricturing/fibrotic pattern predominates. For UC patients, anti-TNF drugs should not be stopped if IM therapy cannot be held.