Sustained Steroid-free Remission Research Articles

P566 Maintenance vedolizumab treatment in pediatric IBD: 54-week follow-up of the prospective multicenter VEDOKIDS study

Abstract Background Prospective long-term data on vedolizumab (VDZ) in children with Crohn’s disease (CD) and ulcerative colitis (UC) are lacking. In this prospective, multicenter cohort study, we aimed to evaluate the effectiveness and safety of maintenance therapy with VDZ in pediatric CD and UC. Methods Children commenced on VDZ were followed at baseline and 2, 6, 14, 30 and 54 weeks thereafter. Serum for drug levels and stool for calprotectin were repeatedly obtained. The primary outcome was sustained steroid-free remission (SSFR), defined as clinical remission )PUCAI<10 or wPCDAI<12.5) without steroids/EEN at both 30 and 54 weeks, analyzed under the ITT principle. Results 139 children were enrolled (77 [55%] UC, 62 [45%] CD; age 14.9 years (IQR 12.0-16.6). Of the 119 (86%) children >30kg, 110 (92%) received a dose of 300mg; 20 (14%) weighed<30 kg and received a dose of 8.3mg/kg (IQR 7–10.3). Week-54 remission rate was 52% in UC and 37% in CD; SSFR rates were 42% and 24%, respectively (OR 2.2 [95%CI 1.1-4.7] Figure). SSFR rate was numerically higher in isolated colonic CD than in ileal disease (5/11 [45%] vs 10/49 [20%], OR 3.3 [95%CI 0.8-12.9]; p=0.08). Infusion interval was shortened in 22 children (10 [13%] UC, 12 [19%] CD), of whom none achieved SSFR. SSFR rate was higher in week-6 responders compared to non-responders in UC (51% vs 27%, OR 2.9 [1.1-7.7]) and CD (35% vs 14%, OR 3.4 [95%CI 0.95-12.4]), similar to the week-14 figures (UC: 50% vs 22%, OR 3.6 [1.2-11.1]; CD: 36% vs 8%, OR 6.2 [1.3-30.8]). SSFR was eventually achieved in 49% of UC children having mild disease at week-6 and 14% with moderate-severe disease (OR 5.8 [95%CI 1.2-28.2]); the corresponding rates in CD were 31% and 0% (p=0.02). In multivariable models, the best predictors in CD were lower wPCDAI at baseline (AUROC 0.88 [95%CI 0.79-0.96]; optimal cutoff 25 (sens/spec 76%/80%)) and at week 6 (0.90 [0.82-0.98]; optimal cutoff 17.5 (80%/87%)). In UC, the best predictors were PUCAI at week 6 (0.70 [0.57-0.82]; optimal cutoff 10 (64%/57%)) and at week-14 (0.78 [0.67-0.89]; optimal cutoff 5 (76%/60%; Table). In children <30kg, SSFR was associated with week 6 drug levels >30ug/mL, not reaching statistical significance (3/6 [50%] vs 1/8 [13%], OR 7.0 [95%CI 0.5-97]). By week 54, 197 adverse events were recorded, of which were VDZ-related in 8 (5.8%) children, and in 2 (1.4%) led to stopping VDZ; none were severe. There was 1 lymphoma case judged to be unrelated to VDZ. Conclusion VDZ was effective for maintaining remission, more so in UC and in colonic CD. The likelihood of eventually achieving SSFR was very low in children with moderate-severe disease or those not showing response at week-6, particularly in CD.

P766 No difference in progression of disability 2 years after stopping infliximab or immunosuppressant vs. continuing combination therapy in patients with CD in sustained steroid-free remission: a subanalysis of SPARE

Abstract Background In the SPARE trial, the discontinuation of infliximab (IFX) in patients with Crohn’s disease (CD) in sustained remission under combination therapy (IFX and immunosuppressant therapy), was associated with a significantly higher relapse rate than when continuing combination therapy or discontinuing immunosuppressant therapy. However, a high proportion of patients rapidly recover remission when resuming treatment. The impact of this treatment strategy on functional disability, a major endpoint in assessing CD progression, has been poorly studied. We aimed to compare the evolution of the IBD-disability index (IBD-DI) in patients continuing combination therapy, discontinuing IFX or immunosuppressant therapy. Methods The study of the evolution of the IBD-DI in the 3 groups (combination, IFX withdrawal, immunosuppressant withdrawal), between baseline and the end of study (2 years), was a pre-defined secondary endpoint of the trial. Changes in scores (between baseline and the end of study) were compared using Wilcoxon tests between the arms “combination group” versus “IFX withdrawal group” and between “immunosuppressant withdrawal group” versus “IFX withdrawal group”. Results IBD-DI was available at baseline and at the end of study for 153 patients out of the 211 randomised in the SPARE trial between November 2015 and April 2019 (46 in the combination group, 55 in the IFX withdrawal group, and 52 in the immunosuppressant withdrawal group) and those were included in the analysis. Table 1 summarizes baseline characteristics of these patients. 30 patients had a relapse (6 [13%] of 46 in the combination group, 19 [34.5%] of 55 in the IFX withdrawal group, 5 [9.6%] of 52 in the immunosuppressant withdrawal group). Of 23 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 21 patients (1 of 2 in the combination group, 18 of 19 in the IFX withdrawal group, and 2 of 2 in the immunosuppressant withdrawal group). The median IBD-DI at baseline was 12.5 (IQR, 5.36-21.43), without significant differences between the 3 groups. Figure 1 shows changes in the IBD-DI between baseline and the end of study in the 3 groups. There was no significant difference in terms of changes in IBD-DI between the arms "combination group" and "IFX withdrawal group" (p=0.56), or between the arms "immunosuppressant withdrawal group” and "IFX withdrawal group" (p=0.29). Conclusion In patients with CD in sustained steroid-free remission under combination therapy with IFX and immunosuppressant therapy, there was no difference in progression of disability over 2 years between those who continued combination therapy, stopped IFX or stopped the immunosuppressant with the possibility of recycling the medication after a relapse.

P938 Effectiveness and safety of switching from original infliximab to GP1111 biosimilar in inflammatory bowel diseases – prospective, cohort study

Abstract Background Biosimilars are highly similar to the already approved reference biological medication, and are potentially more accessible widespread due to the better cost-effectiveness. However, both the effectiveness and immunogenicity may differ due to structure characteristics. In 2020, non-medical switch was obligated from originator infliximab (IFX) to biosimilar GP1111 amongst inflammatory bowel disease (IBD, Crohns’s disease [CD], ulcerative colitis [UC]) patients in Hungary. As data regarding GP1111 are lacking in IBD, thus we aimed to assess the pharmacokinetics, effectiveness and safety of biosimilar GP1111 following the financial switch. Methods This was a real-world, prospective, single-center cohort study enrolling IBD patients who were switched from original IFX to GP1111 biosimilar. Baseline was defined as the day of the switch, and 52 weeks of follow-up was set. Demographic and clinical data were recorded at w0, w8, w16, w24, and w52, while infliximab serum levels were measured at baseline and at w52. Primary outcome was change in serum trough level of IFX, while sustained steroid-free remission, loss of response rates and adverse events were secondary outcomes. Results Overall, data of 142 patients were analyzed (median age: 43.1 years [IQR: 32.3 - 49.6]; male/female ratio: 77/65; CD: 97, UC: 42). Mean follow-up period was 46.2 ± 10.3 weeks. Change in serum IFX level was not observed (baseline 3.2 ± 2.3, µg/mL; w24: 3.7 ± 2.7 µg/mL; p = 0.106). Sustained steroid-free remission rates did not alter at w52 (99/142) from baseline (86/142) (p = 0.11). Overall, treatment was ceased in 24 patients. Following dose escalation and intensification, 9/18 patients discontinued treatment due to loss of response. Further treatments were ceased in 15 patients due to allergy (8), paradoxical reactions (3), malaise (1), pregnancy (1), and non-compliance (2). At w52 83.1% of the patients were on drug, and treatment persistence was not associated with the length of prior IFX treatment period. Conclusion Our study revealed convincing effectiveness with reassuring safety profile of switching to GP1111 in long-term, with sustained IFX levels. The usage of this particular biosimilar in daily practice may be suggested.

IIS Registry Grant Risk of relapse and retreatment success after vedolizumab discontinuation in IBD patients in long-standing remission

Abstract Background and Aims Treatment withdrawal and “cycling” of anti-TNFs has been extensively investigated in the recent years. To date, none or scarce data are available for biological agents other than anti-TNFs, such as vedolizumab (VDZ), which is the first non-anti-TNF agent approved for the treatment of inflammatory bowel disease (IBD). Our aim will be to investigate the risk of relapse and retreatment success in IBD patients that discontinue vedolizumab due to sustained steroid-free remission. Methods This will be a prospective observational study in which two groups of patients in sustained remission will be formed, i.e., patients stopping vedolizumab and patients continuing the treatment. Differences regarding rates of disease flares, IBD-related hospitalisations and surgeries will be analysed. The rate of retreatment success in patients presenting a flare after discontinuation will also be recorded. In addition, potential predictive factors of disease relapse will be investigated to provide future guidance on the patient profile that might benefit the most from intermittent VDZ treatment. The study will last 3 years in total, with the first year dedicated to patient inclusions. Anticipated Impact Only few data are currently available regarding intermittent treatment with vedolizumab. Therefore, this study may provide insights on when to interrupt this biologic with high probability of maintaining remission, while also showing high-risk features that would suggest against stopping the treatment. The use of treatment cycles may represent an impactful cost reduction for our healthcare systems as well as a decrease of potential side effects that are an inevitable consequence of years of immunosuppression.

Improved Clinical Outcomes With Early Anti-Tumour Necrosis Factor Alpha Therapy in Children With Newly Diagnosed Crohn's Disease: Real-world Data from the International Prospective PIBD-SETQuality Inception Cohort Study.

Treatment guidelines for paediatric Crohn's disease [CD] suggest early use of anti-tumour necrosis factor alpha [anti-TNFα] in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. Children with newly diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF [<90 days after diagnosis] and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission [SSFR] without treatment intensification [specified as SSFR*] and sustained steroid-free mild/inactive disease without treatment intensification [specified as SSFMI*]. Penalised logistic regression model-based standardisation was applied to estimate the relative risks [RR] of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients, based on presence of predictors of poor outcome [POPOs] and disease activity at diagnosis. In total, 331 children (median age 13.9 years [IQR 12.2-15.3]) were enrolled, with 135 [41%] receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* [30% vs 14%, p <0.001] and SSFMI* [69% vs 33%, p <0.001], with RRs of 2.95 [95% CI 1.63-5.36] and 4.67 [95% CI 2.46-8.87], respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared with mild/inactive disease at diagnosis (5.50 [95% CI 2.51-12.05] vs 2.91 [95% CI 0.92-9.11]), and those with any POPO compared with no POPO (5.05 [95% CI 2.45-10.43] vs 3.41 [95% CI 0.54-21.7]). In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Real-World Experience With Tofacitinib Dose De-Escalation in Patients With Moderate and Severe Ulcerative Colitis

Tofacitinib is associated with sustained steroid-free remission in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen. We aimed to evaluate predictors and outcomes of disease activity after tofacitinib dose de-escalation in this population. Included were adults with moderate-severe UC treated with tofacitinib between June 2012 and January 2022. The primary outcome was evidence of UC disease activity-related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch. Among 162 patients, 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily. Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P= .81). In univariable Cox regression among patients with dose de-escalation, an induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37; 95% CI, 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41; 95% 95% CI, 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05; 95% CI, 2.00-18.35). Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months. In this real-world cohort, we observed a 56% cumulative incidence of UC events at 12 months in patients with tofacitinib dose de-escalation. Observed factors associated with UC events after dose de-escalation included induction course for fewer than 16 weeks and active endoscopic disease 6 months after initiation.

REAL-WORLD EXPERIENCE WITH TOFACITINIB DOSE DE-ESCALATION IN PATIENTS WITH MODERATE AND SEVERE ULCERATIVE COLITIS

Tofacitinib is associated with sustained steroid-free remission and improved quality of life in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there is limited real-world data to guide decision on optimal maintenance dose. We aimed to evaluate treatment outcomes of tofacitinib dose de-escalation in patients with UC in a real-world cohort.

REAL-WORLD EXPERIENCE WITH TOFACITINIB DOSE DE-ESCALATION IN PATIENTS WITH MODERATE AND SEVERE ULCERATIVE COLITIS

Abstract BACKGROUND Tofacitinib is associated with sustained steroid-free remission and improved quality of life in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there is limited real-world data to guide decision on optimal maintenance dose. We aimed to evaluate treatment outcomes of tofacitinib dose de-escalation in patients with UC in a real-world cohort. METHODS Included were adults with moderate-severe UC treated with tofacitinib between 1/2012-1/2022. Duration of treatment induction with 10 mg twice daily was 8, 16, or &amp;gt;16 weeks. Dose de-escalation was defined as decrease to 5 mg twice daily. Primary outcome was UC flare, defined as UC-related hospitalization/surgery, reinduction with tofacitinib dose increase, corticosteroid, or change of therapy class. Predictors of UC flare were explored using univariable and multivariable Cox regression. RESULTS Among 162 patients, 54% were male and 71% were white with a median age of 38 years, with 41% and 51% having moderate and severe UC, respectively. Eighty-three (52%) patients continued induction dose while 79 (48%) underwent dose de-escalation. There was no significant difference in number of prior biologic use or baseline endoscopic Mayo score, however, patients who underwent de-escalation were less likely to be steroid dependent during induction (50% vs 70%,p=0.01). After a median follow-up of 12 months, cumulative incidence rates of UC flare at 12 months were similar in patients with and without dose de-escalation (56% vs 58%,p=0.81), though patients without dose de-escalation had higher rates of UC-related hospitalization (27% vs 14%,p=0.04) and change of therapy class (39% vs 12%,p&amp;lt;0.01) compared to those who de-escalated. Among patients with dose de-escalation, cumulative rates of UC flare at 12 months were higher in patients with ongoing severe disease (Mayo 3) at 6 months of tofacitinib (Figure 1). In univariable Cox regression, prolonged duration of induction course with 10 mg twice daily &amp;gt;16 weeks was protective of UC flare (HR 0.37,95% CI 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC flare (HR 6.41,95% CI 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and use of corticosteroid at dose de-escalation (HR 6.05, CI 2.00-18.35) (Table 1). Twenty-seven (29%) patients with UC flare had dose re-escalated to 10 mg twice daily with 63% recapturing clinical response at 12 months. CONCLUSIONS In this real-world cohort of UC patients with tofacitinib de-escalation, we observed a 56% cumulative incidence of UC flare at 12 months. Observed factors associated with UC flare after dose de-escalation included shorter induction course &amp;lt;16 weeks and active disease at 6 months of tofacitinib. The majority were able to recapture clinical response after dose re-escalation.

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial

The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. European Union's Horizon 2020.

Distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with Crohn’s disease stopping infliximab: when the remission state hides different types of residual disease activity

ObjectiveDespite being in sustained and stable remission, patients with Crohn’s disease (CD) stopping anti-tumour necrosis factor α (TNFα) show a high rate of relapse (~50% within 2 years). Characterising non-invasively...

P146 Initial response to induction treatment more important than type of induction treatment for achieving sustained steroid free remission at 1 year in new-onset paediatric Crohn’s disease

Abstract Background For paediatric patients with high risk of complicated Crohn’s disease (CD) [stricturing or penetrating disease], paediatric guidelines recommend upfront anti-tumor necrosis factor-alpha (ATA). Early ATA therapy has been demonstrated to result in higher steroid- and surgery-free remission rates at 1 year than induction with conventional treatment (CONV) [Exclusive Enteral Nutrition (EEN) or corticosteroids followed by immunomodulatory therapy]. However, it is unknown whether either type of induction treatment or achieving steroid free remission (SFR) at 3 months is a more important predictor of sustained SFR (SSFR) at 1 year. Therefore, we aimed to evaluate the independent effect of early ATA use after achieving induction of remission on sustained SFR (SSFR) rates at 1 year in an international prospective observational study. Methods Since January 2017, children (0–18 years) with newly-diagnosed CD were prospectively enrolled in 28 European and Asian paediatric IBD centers. Extensive demographic and clinical data were collected at baseline, and at 1, 3, 6 and 12 months. The primary outcome was SSFR at 1 year, defined as a weighted Paediatric CD Activity Index (wPCDAI) &amp;lt;12.5 without steroids at 3, 6, and 12 months. Secondary outcomes included SFR at 3 and 12 months, and treatment escalation to ATA. Outcomes were compared between the early ATA induction treatment group (defined as ATA within 3 months after diagnosis) and the CONV induction treatment group (EEN or corticosteroids), using χ 2 tests. Results Up to July 2021, 235 children with new-onset CD were included and completed at least 1 year of follow-up (61.7% male, median age 13.7 [IQR 11.4–15.0]). At 1 year, 62/203 (30.5%) achieved SSFR. Patients that received early ATA were more likely to achieve SSFR compared to patients with CONV (35/79 [44%] vs. 27/110 [25%], p=0.004). After induction treatment, 99/213 [47%] achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months (48/84 [57%]) than those with CONV (51/129 [40%], p=0.012), and higher rates of low faecal calprotectin (67% vs. 17%, p&amp;lt;0.001) or low CRP (&amp;lt; 5 mg/l) (82% vs. 53%, p&amp;lt;0.001). Of those patients in SFR at 3 months, 71% achieved SSFR, which was not significantly different between those in SFR at 3 months with early ATA vs. with CONV (35/45 [78%] vs. 27/43 [63%], p=0.12). Conclusion While only one-third of paediatric CD patients achieve SSFR at 1 year, 71% of patients achieve SSFR after having achieved SFR at 3 months. Patients with early ATA had higher rates of SFR at 3 months and SSFR at 1 year than those without early ATA. Remission at 3 months was found to be more important for SSFR than type of induction treatment, highlighting the importance of initial response to induction treatment.

OP01 Withdrawal of infliximab or anti-metabolite therapy in Crohn’s Disease patients in sustained remission on combination therapy: A randomized unblinded controlled trial (SPARE)

Abstract Background Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy. Methods CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite &amp;gt; 8 months and in sustained steroid-free remission &amp;gt; 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission). Results 254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4–23%) in arm A, 40% (IC95%: 28–51%) in arm B, and 10% (IC95%: 2–18%) in arm C (p=0.0003 arm B vs arm A and &amp;lt;0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83–1.99), 1.89 yrs (IC95%: 1.82–1.96) and 1.93 yrs (IC95%: 1.86–2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C. Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B. Conclusion Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy. Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

P494 A serum metabolite panel predicts Crohn’s disease relapse in patients discontinuing infliximab and continuing antimetabolite therapy: sub-analysis of the SPARE Trial

Abstract Background Combination therapy with infliximab and anti-metabolites is an effective strategy for maintaining remission in patients with Crohn’s disease (CD); however, the implications of long-term combination therapy has led clinicians to consider discontinuing one of the two agents after sustained remission has been achieved. The SPARE investigators have addressed this in an unblinded clinical trial in which 211 patients were randomised to either continuation of combination therapy, withdrawal of infliximab, or withdrawal of antimetabolite therapy. Here, we aimed to determine whether nuclear magnetic resonance (NMR)-based metabolomics analysis of patient sera at baseline could determine which patients randomised to infliximab withdrawal would relapse over 2-years on anti-metabolite monotherapy. Methods The study cohort comprised patients randomised to infliximab cessation who had a serum aliquot available for analysis (n=63). All patients had been treated with a combination therapy of infliximab (IFX) and anti-metabolite &amp;gt;8 months and had been in sustained steroid-free remission &amp;gt;6 months. Disease relapse was defined by CDAI&amp;gt;250 (or between 150–250 with 70 points increase over two consecutive weeks) alongside serum CRP and faecal calprotectin levels. Untargeted metabolomic profiling was carried out using NMR spectroscopy. Key metabolites were identified by their variable importance in projection (VIP) score using orthogonal partial least squares discriminant analysis (OPLS-DA) with 10-fold cross-validation on independent data. Multiple logistic regression on the metabolites with highest VIP score was used to report a receiver operator characteristic (ROC) curve integral (AUC) value after collinear variables were removed. Results Of 63 patients, 21 (33%) relapsed. The mean time to relapse after infliximab discontinuation was 7.9 months. Four independent (multicollinearity R2&amp;lt;0.4) serum metabolites (alanine, glutamine, acetoacetate, glucose) identified relapse with an AUC of 0.84 (95% confidence interval 0.74–0.94, p&amp;lt;0.0001). The positive predictive value was 66.7%, and the negative predictive value was 77.1%. All serum metabolites identified were independent of baseline CRP level (p&amp;gt;0.05, Pearson correlation). Patients who relapsed following infliximab discontinuation had significantly elevated serum acetoacetate and decreased alanine and glutamine levels (post-hoc students t-test, p&amp;lt;0.05) at baseline. Conclusion Here, we identify a panel of serum metabolites independent of baseline serum CRP, which predict high risk of disease relapse after infliximab discontinuation. These data may help in stratifying patients suitable for drug withdrawal, together with other clinical and multi-omic parameters.

The impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis clinical programme.

SummaryBackgroundObesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC.AimsTo assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI).MethodsThis post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8‐week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52‐week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (<25, 25 to <30 and ≥30 kg/m2). Outcomes included remission, endoscopic improvement, clinical response, sustained steroid‐free remission, Inflammatory Bowel Disease Questionnaire total score and Short Form‐36 Health Survey scores. Adverse events were evaluated.ResultsAt Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 5 or 10 mg twice daily (b.d.) achieved clinical response vs placebo, regardless of baseline BMI subgroup (all P < 0.05). Proportions of patients achieving efficacy endpoints were generally similar across BMI subgroups; in univariate and multivariate regression analyses, BMI was not a significant predictor (all P ≥ 0.05; univariate BMI [continuous] odds ratio for remission: 0.98 [95% confidence interval 0.95, 1.02]). There was no consistent trend between BMI and adverse events. Among patients receiving tofacitinib 10 mg b.d. in OCTAVE Induction 1 and 2, serious infections were numerically greater in the BMI ≥30 subgroup (3.2%) vs other subgroups (0.4%). Limitations included small patient numbers in the BMI ≥30 subgroup.ConclusionsEfficacy and safety of tofacitinib were similar in patients with UC regardless of baseline BMI.

Cytapheresis re-induces high-rate steroid-free remission in patients with steroid-dependent and steroid-refractory ulcerative colitis.

BACKGROUNDIt is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients.AIMTo clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients.METHODSWe retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger’s clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test.RESULTSThe rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger’s clinical activity index scores were significantly decreased after CAP (P < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period.CONCLUSIONOur results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.

Living with ulcerative colitis in Germany: a retrospective analysis of dose escalation, concomitant treatment use and healthcare costs

Aims: To investigate treatment of moderate-to-severe ulcerative colitis (UC) using real-world German health insurance claims data.Materials and methods: A retrospective, longitudinal cohort study was conducted from a German statutory health insurance database for adult patients with UC indexed on biologic therapy initiation (2013–2015). Anonymized data were evaluated for 12 months prior to (baseline) through 24 months after (follow-up) indexing. Biologic dose escalations, steroid and immunosuppressant use, healthcare resource utilization (HCRU) and direct healthcare costs were evaluated, with significant differences assessed across and between index biologics. Descriptive statistics, chi-square or Fisher’s exact tests, and analysis of variance were performed.Results: The analysis included 304 patients (adalimumab, n = 125; golimumab, n = 47; infliximab, n = 114; vedolizumab, n = 18). Demographic and clinical characteristics were similar across biologics. Dose escalations occurred in 58% of patients (73% of patients receiving adalimumab), with 41% receiving subsequent de-escalation. Steroids were used during follow-up by 74% of patients; 25% received steroids >14 weeks after indexing. Overall, 41% of patients received an immunosuppressant during follow-up. Steroid and immunosuppressant use were similar across biologics. Total direct healthcare costs were higher during follow-up than baseline and differed significantly across treatments (p < .05), with highest costs for golimumab. Biologic costs contributed to a major portion of follow-up costs. HCRU and costs for most resources were higher in the first 12-month follow-up period than baseline. All resource use except gastroenterology visits returned to, or below, baseline levels 13–24 months post-index date.Limitations: There was potential for inappropriate inclusion/exclusion due to miscoding. Patients may have received biologics >12 months prior to the index date. Biologic originators and biosimilars could not be differentiated.Conclusions: These data suggest that control with current biologics is suboptimal. Further treatment options that provide sustained steroid-free remission for this patient population without the need for dose escalations or concomitant therapies may be warranted.

Sustained Steroid Free Remission at One Year in Corticosteroid Dependent Ulcerative Colitis Patients on Vedolizumab

Sustained Steroid Free Remission at One Year in Corticosteroid Dependent Ulcerative Colitis Patients on Vedolizumab

Combination Antibiotics Improves Disease Activity and Alters Microbial Communities in Children With Ulcerative Colitis.

Combinations of antibiotics have shown promise in off-label treatment of Inflammatory Bowel Disease (IBD) flares in adult and pediatric patients1–6. In a small pediatric cohort of moderate-severe medically refractory Ulcerative Colitis (UC), half achieved remission with a regimen of 3–4 antibiotics6. The rationale is to decrease mucosal inflammation by altering intestinal microbiota, however, to date no study has documented these changes. We report our experience with combination oral antibiotics in symptomatic pediatric patients with steroid-dependent or -resistant UC, and demonstrate significant alterations in gut microbiota during and after antibiotic therapy with reductions in inflammatory markers.

Efficacy of Tofacitinib in Patients With Ulcerative Colitis by Prior Tumor Necrosis Factor Inhibitor Treatment Status: Results From OCTAVE Induction and Maintenance Studies

Introduction: Many patients (pts) with ulcerative colitis (UC) treated with tumor necrosis factor inhibitors (TNFi) do not respond to initial therapy (primary non-response [NR]) or experience loss of response over time (secondary NR).1 Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for UC. Methods: Pts in OCTAVE Induction 1 & 2 with moderately to severely active UC who failed or were intolerant to steroids, immunomodulators or TNFi received placebo (PBO; N=234) or tofacitinib 10 mg twice daily (BID; N=905) for 8 weeks (wks). In OCTAVE Sustain, induction study clinical responders were rerandomized to PBO (N=198), tofacitinib 5 mg BID (N=198) or 10 mg BID (N=197) for 52 wks. Corticosteroids were allowed in OCTAVE Induction; corticosteroid taper was mandatory in OCTAVE Sustain. Subgroup analyses by prior TNFi failure status were conducted for remission, mucosal healing and clinical response at Wk 8 (OCTAVE Induction; pooled data) and Wk 52 (OCTAVE Sustain), and sustained steroid-free remission among remitters at baseline of OCTAVE Sustain. Between-group treatment differences and 95% confidence intervals using the normal approximation were calculated, as well as p values based on chi-square test. Results: At Induction baseline, 51.7% of pts had failed TNFi (of whom 55.7% had primary NR, 39.2% secondary NR and 32.6% ≥2 failed TNFi). At Wk 8 of OCTAVE Induction, consistent treatment effects were observed with tofacitinib 10 mg BID vs PBO for all endpoints and categories of prior TNFi treatment status (Table). Observed treatment effects for remission, mucosal healing and clinical response were similar for pts with and without prior TNFi failure, and for pts who failed 1 TNFi and who failed ≥2 TNFi. In OCTAVE Sustain, treatment effects were observed at Wk 52 for 5 mg and 10 mg vs PBO for all endpoints and TNFi treatment categories. Treatment effects in OCTAVE Sustain were generally greater for 10 mg BID vs 5 mg BID, especially in pts with prior TNFi failure.Table: Table. Efficacy in OCTAVE Induction and OCTAVE Sustain Stratified by Prior TNFi Treatment StatusConclusion: Tofacitinib was efficacious vs PBO as induction and maintenance therapy, regardless of prior TNFi failure. Benefits over PBO were apparent even in the most refractory populations, including induction of remission in pts with primary NR, and pts who had failed ≥2 TNFi. Funded by Pfizer Inc. 1. Roda G et al. Clin Trans Gastroenterol 2016:e135.

Tofacitinib for Maintenance Therapy in Patients With Active Ulcerative Colitis in the Phase 3 OCTAVE Sustain Trial: Results by Local and Central Endoscopic Assessments

Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). A Phase 3, randomized, double-blind, placebo-controlled maintenance study (OCTAVE Sustain, NCT01458574) demonstrated the efficacy of tofacitinib 5 and 10 mg twice daily (BID) vs placebo (PBO) in patients (pts) with moderate to severe UC.1 Methods: We describe clinical efficacy endpoints assessed by local endoscopy readings and previously reported results assessed by central readings, to compare local vs central readings in the assessment of tofacitinib efficacy. Pts who completed OCTAVE Induction 1 (NCT01465763) or OCTAVE Induction 2 (NCT01458951) studies and achieved clinical response (decrease of baseline Mayo score ≥3 points and ≥30%, with decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1) were eligible to participate in OCTAVE Sustain. 593 pts were randomized (1:1:1) to PBO, tofacitinib 5 or 10 mg BID for 53 weeks (wks). Pts' eligibility was assessed based on central endoscopic reading. Pts were permitted concomitant treatment with oral corticosteroids; tapering was mandatory from baseline. Concomitant treatment with immunosuppressants and biologics was prohibited. Efficacy endpoints at Wk 52 included remission (primary endpoint: Mayo score ≤2, no subscore >1 and rectal bleeding subscore of 0), mucosal healing (Mayo endoscopic subscore ≤1) and clinical response. Results: At Wk 52, remission was achieved by significantly more pts with both tofacitinib doses vs PBO, as demonstrated by both central and local endoscopic readings, and similar results were observed with mucosal healing, clinical response and sustained steroid-free remission among pts in remission at baseline. Efficacy assessed by local endoscopic readings was numerically greater than central readings, except for clinical response. There was good agreement between locally and centrally read endoscopic subscores (kappa=0.6 [95% CI 0.5, 0.6]). Conclusion: Efficacy assessed by local endoscopic readings was numerically greater than efficacy assessed by central readings for tofacitinib 5 and 10 mg BID vs PBO. Overall, local endoscopic readings were consistent with central readings. Both methods demonstrated that both tofacitinib doses were more effective than PBO for maintenance therapy in pts with moderately to severely active UC. Funded by Pfizer Inc.Table: Table. Summary of efficacy endpoints at Wk 52, determined by local and central reading