Achievement Of Clinical Remission Research Articles

#212 The clinical significance of circulating piRNAs in extracellular vesicles in patients with idiopathic membranous nephropathy

Abstract Background and Aims Of various small RNAs, many miRNAs have been studied as potential biomarkers for various renal diseases. However, there are few literatures about P-element-induced wimpy testis-interacting RNAs (piRNAs), which are the most recently discovered class of small RNAs. Therefore, we investigated the clinical significance of piRNAs in idiopathic membranous (IMN) patients. Method We prospectively enrolled 60 participants, including those with IMN (n = 19) and idiopathic nephrotic syndrome (INS; n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum extracellular vesicle (EV)-piRNA profiles of all participants. We investigated whether the piRNAs could be helpful to discriminate IMN from INS and predict the treatment response of patients with IMN. Based on achievement of clinical remission, IMN patients were divided in to two groups: a well-responding (IMN-W) and refractory (IMN-R) group [IMN-W (n = 9) vs IMN-R (n = 10)]. Results We found 11 piRNAs that were upregulated and 6 that were downregulated in patients with IMN when compared to HVs. There were 22 miRNAs that were upregulated and 23 that were downregulated in patients with IMN when compared to the INS. Among these miRNAs, we found 5 piRNAs, whose levels were significantly up- or downregulated in patients with IMN compared to HVs and patients with INS. There were 50 upregulated and 11 downregulated piRNAs in patients with IMN-R when compared to patients with IMN-W. Of these piRNAs, the expression level of piRNA-42775 and piRNA-36743 were found to be inversely correlated with proteinuria on kidney biopsy. Meanwhile, a positive correlation was observed between renal function and expression of piRNA-43108. Conclusion Patients with IMN have a distinct EV-piRNA expression profile compared with INS and HVs. In addition, circulating EV-piRNAs could be useful to predict the treatment response of IMN patients.

Evaluation of Clinical Remission in Best-Performing Severe Asthmatic Patients Treated for Three Years with Mepolizumab.

In its severe form, where possible, asthma is treated using biological drugs in order to reduce, as much as possible, the use of systemic steroids. Mepolizumab is effective for severe asthma based on key outcomes such as exacerbation and steroid dependence. Its efficacy in terms of the criteria for clinical remission in the short and long term has become of interest. We aimed to evaluate the effect of mepolizumab in the achievement of clinical remission after 3 years of administration. In this study, 71 patients who continued mepolizumab for 3 years were assessed for clinical remission according to six different published sets of remission criteria. According to the criteria, 39-52% of patients experienced complete remission in the first year, increasing to 51-73% at 3 years. By classifying patients according to partial and complete remission criteria, proposed by the SANI, we observe 22% of patients in partial remission at one year, achieving complete remission after three years. The baseline factors associated with earlier remission were a higher FEV1, if we consider classifications requiring an FEV1 ≥ 80%, a low OCS dose, and low FeNO levels, in the patients requiring FEV1 stabilization. Clinical remission is possible for patients treated with mepolizumab. The observations at three years compared with the first year indicated that the factors negatively affecting remission delayed rather than prevented it. Earlier treatment could increase the chances of remission.

Effectiveness and safety of upadacitinib for inflammatory bowel disease: A systematic review and meta-analysis of RCT and real-world observational studies

BackgroundUpadacitinib, a novel and selective inhibitor of Janus kinase 1, has demonstrated promising efficacy in managing inflammatory bowel disease (IBD). In this systematic review and meta-analysis, our primary aim was to comprehensively assess the therapeutic effectiveness and safety profile of upadacitinib in the treatment of patients with IBD. MethodsWe conducted an extensive literature search across prominent databases, including Medline, Embase, Web of Science, and Cochrane Central, to identify pertinent studies providing insights into the efficacy and safety of upadacitinib in IBD. The primary endpoint was the achievement of clinical remission, while secondary endpoints encompassed clinical response, endoscopic response, endoscopic remission, and the evaluation of adverse events (AEs). ResultsIn this meta-analysis of nine studies, we categorized results by study type. Clinical remission rates were: RCTs 36 % (95 % CI = 30–42 %), real-world studies 25 % (95 % CI = 1–49 %), retrospective studies 40 % (95 % CI = 24–56 %), cohort studies 55 % (95 % CI = 25–85 %). Clinical response rates were: RCTs 61 % (95 % CI = 55–67 %), real-world studies 42 % (95 % CI = 14–70 %), cohort studies 65 % (95 % CI = 57–73 %). Endoscopic remission rates were: RCTs 19 % (95 % CI = 15–24 %), cohort studies 29 % (95 % CI = 5–52 %). Endoscopic response rates were: RCTs 41 % (95 % CI = 36–47 %), cohort studies 57 % (95 % CI = 31–83 %). Incidence rate for any AEs: IBD 69 % (95 % CI = 63–76 %), UC 65 % (95 % CI = 57–74 %), CD 75 % (95 % CI = 67–82 %). ConclusionCumulative data from real-world studies and trials confirm the efficacy of upadacitinib in IBD induction and maintenance, with consistent safety. However, further long-term studies are needed to understand its sustained effectiveness and safety.

Symposium 3

Systemic sclerosis (SSc) remains a refractory condition with poor functional and survival outcomes. This is attributable primarily to the extremely diverse clinical course and distribution of organ involvement. The pathogenesis of SSc includes microangiopathy and chronic inflammation, leading to accumulation of extracellular matrix and resultant irreversible fibrosis resulting in distortion of the normal tissue architecture. This pathogenic process is analogous to that observed in rheumatoid arthritis, in which persistent synovitis leads to articular cartilage and bone destruction, resulting in functional impairment due to joint deformity. Therefore, successful experiences in developing treatment strategies in patients with rheumatoid arthritis can also be applied to SSc. These include early diagnosis and intervention, treat-to-target strategy aiming at achievement of clinical remission or low-disease activity, prediction of disease progression and prognosis, and disease modification by pharmacologic treatment. Immunosuppressants targeting lymphocytes, including mycophenolate mofetil and cyclophosphamide, have been the mainstream of the treatment of SSc, based on treatment evidence showing prevention of decline in forced vital capacity, promotion of improving modified Rodnan skin thickness score, and improved patient-reported outcomes. However, survival benefit has not been shown in long-term follow-up of patients treated with non-specific immunosuppressants. Recently, drugs targeting a variety of molecules involved in the pathologic process of SSc, such as tocilizumab and nintedanib, have been shown to prevent progression of certain organ involvement in clinical trials, resulting in expanding treatment options. Implementation of those potential disease-modifying therapies in management of SSc requires adequate assessment of disease activity and treatment goal setting. In addition, clinical characteristics that predict the progression of organ manifestations, such as skin sclerosis and interstitial lung disease, need to be identified as prognosis factors. Like other rheumatic diseases, early interventions have been shown to be more effective than delayed intervention. This lecture features current standings and challenges of treat-to-target strategy in SSc patients.

Upadacitinib as a Novel Treatment in Therapy Refractory Collagenous Colitis.

Microscopic colitis (MC) is an inflammatory disorder of the colon histologically subclassified into lymphocytic colitis (LC) and collagenous colitis (CC).1,2 Budesonide is an effective first-line treatment in both forms of MC. However treatment-refractory disease, particularly in CC, remains a challenging clinical problem.3,4 Janus kinase (JAK) inhibitors are novel small molecules approved for the management of ulcerative colitis that have a rational mechanistic basis for treatment of MC based on the role of interferon-γ in disease pathogenesis.5 One recent case report described the use of upadacitinib, a selective JAK1 inhibitor, in LC.6,7 However, to date no reports exist about the effectiveness of JAK inhibitors for refractory CC. Here, we describe a patient with refractory CC who rapidly achieved clinical remission on upadacitinib. The patient was a 75-year-old woman with a history of hypothyroidism who developed watery diarrhea (4-8 bowel movements per day, Bristol Stool Scale type 7) accompanied by fecal incontinence in 2014. She was diagnosed with CC based on colonoscopy with biopsies, after ruling out celiac disease and infectious etiologies. Treatment with budesonide, cholestyramine, bismuth subsalicylate, loperamide, and later prednisone 40 mg daily resulted in a slight decrease in stool frequency, but she continued to experience urgent liquid stools and fecal incontinence that greatly impaired her quality of life. She was next treated with dose-optimized adalimumab, vedolizumab, and ustekinumab without meaningful improvement (Figure 1). Because of her refractory symptoms, she was started on upadacitinib 45 mg daily, with achievement of clinical remission by Hjortswang criteria8 for the first time since diagnosis within 1 week of therapy initiation (Figure 1). After 8 weeks of induction dosing, she had 1 to 2 formed (Bristol Stool Scale type 3-5) bowel movements per day with complete resolution of urgency and incontinence. C-reactive protein decreased from 1.1 to <0.1 mg/dL and erythrocyte sedimentation rate from 7 to 3 mm/h. Monitoring labs showed an increase in her transaminases (alanine transaminase from 21 to 40 IU/L and aspartate transaminase from 19 to 40 IU/L) and a drop in hemoglobin (from 13.2 to 11.2 g/dL). Her upadacitinib dose was decreased to 30 mg, then 15 mg daily. On this dose she has remained in clinical remission with hemoglobin normalization and stable transaminases.

A Real-World Study of Achievement Rate and Predictive Factors of Clinical and Deep Remission to Biologics in Patients with Severe Asthma.

Recent advances in biologics have provided new insights into the clinical course of asthma, including disease modification, clinical remission (CR), and deep remission (DR). However, the extent to which biologics achieve CR and DR in severe asthma patients is poorly understood. To assess the achievement rate and predictors of CR and DR using long-term biologics, we retrospectively evaluated 54 severe asthma patients recently started on biologics. "CR" denotes the achievement of all three criteria: (1) absence of asthma symptoms, (2) no asthma exacerbations, and (3) no use of oral corticosteroids. DR denoted CR plus (4) normalized pulmonary function and (5) suppressed type 2 inflammation. CR and DR achievement rates were 68.5% and 31.5%, respectively. Compared with the non-deep remission group, the DR group had higher adult-onset asthma rates (94.1% vs. 70.3%, p = 0.078), shorter asthma duration (5 vs. 19 years, p = 0.006), and higher FEV1 (91.5% vs. 71.5%, p < 0.001). There were no significant differences in the Asthma Control Questionnaire scores, exacerbation frequency, or type 2 inflammation at baseline between groups. Asthma duration combined with FEV1 can stratify the achievement rates of CR and DR. the early introduction of biologics in severe asthma patients may help achieve CR and DR.

Combined Histological and Endoscopic Endpoints at Post-induction Lack Additional Prognostic Value Compared with Endoscopic Improvement Alone in Ulcerative Colitis: A Post hoc Analysis of the VARSITY study.

Evaluating histological outcomes in ulcerative colitis [UC] has become common in recent clinical trials. In this study, we explored the additional value of the combined endpoint of histo-endoscopic mucosal improvement [HEMI] compared with endoscopic improvement [EI] at post-induction [Week 14] and post-maintenance [1 year]. This post hoc analysis included 620 UC participants with available data from the VARSITY trial. Participants achieving post-induction and post-maintenance HEMI [Mayo endoscopic subscore ≤1 and Geboes score <3.2] were compared across clinical outcomes, patient-reported outcomes [PROs], and inflammatory markers. Univariate analyses were performed to identify variables associated with the outcome of interest. Multivariate analyses included covariates with a p <0.05 on univariate analyses. Among the 468 patients with 1-year data available, a total of 166 [35.5%] attained HEMI and 209 [44.7%] attained EI at post-induction. No difference in achievement of clinical remission [CR] at 1 year was observed among those who attained post-induction HEMI vs EI (121/166 [72.9%] vs 147/209 [70.3%], p = 0.903). Similar findings were observed for the outcome of 1-year treatment failure (45/166 [27.1%] vs 55/209 [26.3%], p = 0.781). Patients who achieved HEMI at post-induction had lower total and partial Mayo scores and had the largest improvement from baseline. Faecal calprotectin and C-reactive protein [CRP] were also significantly lower among HEMI achievers at post-induction [p <0.001]. Similar findings were observed at post-maintenance. In this post hoc analysis, at post-induction, HEMI did not demonstrate additional prognostic value in predicting 1-year outcomes over EI. However, HEMI was associated with lower clinical disease activity at post-induction and at 1 year compared with endoscopic or histological outcomes in isolation.

P513 Prospective study on patients’ satisfaction and impact on quality of life of corticosteroid therapy in patients with Inflammatory Bowel Disease

Abstract Background Corticosteroids (Cs) remain the first-line therapy for moderate-to-severe flares in patients with inflammatory bowel disease (IBD), both Crohn’s disease (CD) and ulcerative colitis (UC). On the other hand, their use has been associated to multiple adverse events (AEs) in randomized controlled trials and registries. Nevertheless, recent studies have repeatedly observed that the use of Cs has not decreased in spite of the increasing availability of biological agents and new small molecules licensed for IBD. The impact of Cs therapy on patients’ quality of life (QoL) and the patients’ perception on Cs have not been properly assessed in IBD. The purpose of this study was to assess the impact of a standard Cs course on the patients’ QoL and their satisfaction with treatment. Methods A prospective, longitudinal and observational study was conducted in adult IBD. All subjects received the same standard Cs regimen: starting dose of 1mg/kg/day (maximum 60mg/day) and tapering after 14 days with 10mg per week until reach 20mg/day, thereafter reduction was 5mg per week. QoL was assessed by the IBDQ-9 questionnaire at baseline, week 4 and at the end of Cs. Treatment satisfaction was assessed by the TSQM1.4 questionnaire at week 4 and at the end of Cs. Results Sixty-three patients were included in the study (54% CD and 43% UC; mean age 38.5±14.9 years; 46%females). Cs therapy failed in 41% of cases (active disease upon Cs discontinuation or need for rescue therapy). AEs attributable to Cs were reported in 84.1%, the most frequent were dermatologic (acne and moon face) (60.3%), hypokalemia (44.8%) and poor quality of sleep (40%). Serious AEs were reported in 20,6%, mostly mild or moderate infections that resolved without sequelae. IBDQ-9 scores increased 12.4 and 13.5 points at 4 weeks and at the end of Cs, respectively (p&amp;lt;0.05). Improvement in QoL was not associated with any of the analysed factors (gender, age, type of IBD, response to treatment and AEs). The overall degree of satisfaction with Cs was 68.5 over 100 points, with the highest score related to satisfaction with adverse events (82/100). Satisfaction with treatment was only associated with the achievement of clinical remission or development of steroid dependence. Conclusion A standard Cs course significantly increases the QoL of patients with IBD. Furthermore, a high satisfaction with treatment was perceived by patients.

P505 Real word long-term efficacy and safety of vedolizumab in managing ulcerative colitis versus crohn’s disease: results from “long vedo” italian multicenter study

Abstract Background Current data about long-term use of vedolizumab (VDZ) in ulcerative colitis (UC) versus Crohn’s disease (CD) patients are limited. We aimed to assess whether there are differences in term of long-term efficacy and safety of VDZ in UC vs. CD patients. Methods Clinical activity was scored according to the Mayo score in UC and to the Harvey-Bradshaw Index (HBI) in CD. The primary endpoints were the achievement of clinical remission within 6 month of treatment, maintenance of clinical remission during a long follow-up, and safety. Secondary endpoints were clinical response to treatment, achievement of mucosal healing (MH), steroid discontinuation, and treatment optimization during the follow-up. Results The study group consisted of 729 patients (475 patients with UC and 254 CD patients with CD) with a median follow-up of 18 (interquartile range 6-36) months. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients, higher in CD patients (74.4 vs. 62.9, p&amp;lt;0.000) while, at the maximal follow-up, it was achieved and maintained in 81.5% of patients (UC vs. CD, p=0.667). At uni- and multivariate analysis, reaching clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics were significantly associated with longer clinical remission (p&amp;lt;0.0001). Long-term follow up clinical response was significantly higher in UC vs. CD (p=0.023) and surgery occurred more frequently in CD (p=0.04), while no difference were found between UC and CD about the other secondary endpoints Conclusion Overall, no significant differences were found about the long-term use of VDZ in UC vs. CD. However, we identified some parameters the can help the physician to predict the long-term efficacy of this drug.

Impact of csDMARDs adherence on clinical remission in patients with new-onset inflammatory arthritis: a prospective cohort study from the ELECTRA database.

Major improvements in the management of rheumatoid arthritis (RA) have made clinical remission an achievable and desirable goal but, despite the relevance gained by a profound disease suppression, many patients with RA still miss clinical remission due to several factors influencing disease activity, including treatment adherence. To evaluate the effect of adherence to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on the achievement of clinical remission in a cohort of patients with new-onset inflammatory arthritis. A prospective cohort study was conducted using the ELECTRA database, which consists of clinical data from patients followed at the IRCCS Policlinico San Matteo Foundation (Pavia, Italy), linked to regional administrative healthcare databases. We enrolled patients with new-onset active disease between January 2006 and December 2013 and followed them until their first clinical remission or end of follow-up (December 2015). To assess the association of csDMARD adherence with clinical remission, we estimated the csDMARD proportion of days covered (PDC) during follow-up. PDC was added to the main clinical adjustment covariates as a time-dependent variable in a proportional hazard Cox regression model. The cohort included 324 patients with a mean (SD) age of 58 (13.9) and predominantly female (74.5%). A total of 219 patients (67.6%) achieved clinical remission during follow-up and 85 (26.2%) in the first 6 months (early clinical remission). Cox regression models showed that a 10% increment of PDC increased the probability of achieving clinical remission by 10% (p < 0.001) and the probability of early clinical remission by 21% (p = 0.03). Patients at disease onset with higher adherence to csDMARDs were more likely to achieve clinical remission and early clinical remission. Our study highlighted the importance of close monitoring of patients to increase their likelihood of following therapeutic indications and achieving favorable disease outcomes, such as lower disability.

Health-related quality of life, continuity of care and patient satisfaction: long-term outcomes of former patients of the Tuebingen Transition Program (TTP) – a retrospective cohort study

BackgroundA significant number of patients in pediatric rheumatology suffer from ongoing disease activity into adulthood and thus need to be transferred into adult care. Transition as a structured individual process of preparation and patient empowerment can reduce risks of adverse long-term outcomes. The aim of this study was to measure long-term transition outcomes such as health-related quality of life (HR-QoL), patient satisfaction, and continuity of care in former patients of the interdisciplinary Tuebingen Transition Program (TTP).MethodsIn an iterative team process, a standardized questionnaire was developed including the EQ-5D-5L to measure HR-QoL, visual analogue scales to measure various items of patient satisfaction, further questions on continuity of care and physical activity and physician global assessment (PGA) to determine disease activity. HR-QoL and physical activity were compared to data from the average German population. Data was analyzed descriptively, and a logistic regression analysis was performed to identify possible predictive factors for negative outcomes.ResultsResponse rate was 28.8% (85/295), 70.6% were female and median age was 24.1 years. 70.6% were diagnosed with juvenile idiopathic arthritis (JIA). Overall, HR-QoL was high (79.8 on the EQ VAS), yet lower than in the average population. The study cohort was more physically active than the respective average age groups. Mean patient satisfaction with pediatric care (8.4; standard deviation (SD) 1.7) and with the transition program (7.9; SD 2.6) was higher than with adult care (7.7; SD 2.2). 76.5% of participants received regular rheumatologic care after transfer. After excluding all participants in remission, the drop-out rate was 4.7%. A low PGA at the time of transfer was associated with higher HR-QoL and patient satisfaction after transfer.ConclusionsHR-QoL of adult patients after successful transfer to adult rheumatology is reduced compared to the general population but physical activity and achievement of clinical remission could help to prevent negative long-term outcomes. Patient satisfaction and self-management of TTP patients were generally high, whereas youth-specific issues and their impact on the disease mandate greater attention. Treatment discontinuation rates were low and mostly due to remission. Further studies should focus on the identification of early predictors of long-term outcome to improve the process and outcome of transition.

S16 Association of Quality of Life With Clinical Remission, HEMR, and Bowel Urgency in Patients With Ulcerative Colitis Treated With Mirikizumab

Background: Mirikizumab, a p19-directed anti-IL-23 antibody, has demonstrated efficacy and safety in patients with moderately-to-severely active ulcerative colitis (UC) in the Phase 3 LUCENT-1 induction trial (NCT03518086) and LUCENT-2 maintenance trial (NCT03524092). Secondary analyses of LUCENT trials showed that mirikizumab treated patients had significantly improved quality of life compared to patients with placebo. This analysis evaluated the relationships between quality of life assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and patients’ status of achieving clinical remission, histologic-endoscopic mucosal remission (HEMR), bowel urgency clinically meaningful improvement (CMI), and bowel urgency remission. Methods: In LUCENT-1, 1,281 patients were randomized 3:1 to mirikizumab 300 mg intravenous infusion or placebo every 4 weeks (Q4W). Patients who achieved clinical response to mirikizumab by Week 12 (W12) of induction (N=544), were re-randomized 2:1 to subcutaneous mirikizumab 200mg or placebo Q4W for 40 weeks in LUCENT-2 (52-weeks of continuous treatment). The primary endpoint was proportion of patients with clinical remission at W12 in LUCENT-1 and Week 40 in LUCENT-2. The clinical outcomes of interest in this analysis include: IBDQ (a 32-item patient-completed questionnaire with higher scores indicating better disease-specific quality of life ), clinical remission (stool frequency subscore = 0 or 1 with a ≥1-point decrease from baseline; rectal bleeding subscore = 0; and endoscopic subscore (ES)= 0 or 1), HEMR (Geboes score of ≤2B and ES = 0 or 1), and bowel urgency [assessed using the Urgency Numeric Rating Scale (UNRS), a 11-point scale ranging from 0 (“no urgency”) to 10 (“worst possible urgency”)]. Bowel urgency CMI is a ≥3-point change and bowel urgency remission is a UNRS score of 0 or 1, both among patients with a baseline UNRS of ≥3. Association between IBDQ total score change from baseline and clinical outcomes were assessed at W12 and Week 52 (W52) using analysis of covariance models adjusting for treatment, clinical parameter, baseline IBDQ value, and randomization stratification factors. Results: Overall, significantly greater increase in IBDQ total score were observed in patients who achieved clinical remission, HEMR, bowel urgency CMI or bowel urgency remission compared to those who did not. As for patients treated with mirikizumab, the least square mean (LSM) change of IBDQ total score [LSM(SE)] by clinical outcome status (Yes vs No) were: Clinical Remission: W12: 55.0 (2.02) vs 33.7 (1.16), P< 0.001; W52: 60.7 (2.38) vs 39.8 (2.43), P< 0.001; HEMR: W12: 50.3 (2.15) vs 35.2 (1.19), P< 0.001; W52: 59.3 (2.60) vs 43.4 (2.40), P< 0.001; Bowel Urgency CMI: W12: 52.8 (1.41) vs 27.4 (1.36), P< 0.001; W52: 62.5 (2.20) vs 34.4 (2.77), P< 0.001; and Bowel Urgency Remission: W12: 57.6 (1.92) vs 32.3 (1.15), P< 0.001; W52: 64.9 (2.54) vs 40.8 (2.18), P< 0.001. Placebo-treated patients were similar to the mirikizumab group across the studied clinical outcomes endpoints, with smaller magnitude of IBDQ improvements. Conclusion(s): The achievement of clinical remission, histologic-endoscopic mucosal remission, bowel urgency clinically meaningful improvement and bowel urgency remission was associated with significant improvement in quality of life by IBDQ in patients with UC from LUCENT-1 and 2 trials.

S948 Relationship Between Hospitalization, Surgery and Achievement of Clinical Remission or Clinical Response in Moderate to Severe Crohn’s Disease Patients: Results From the UNITI/IM-UNITI Trials

S948 Relationship Between Hospitalization, Surgery and Achievement of Clinical Remission or Clinical Response in Moderate to Severe Crohn’s Disease Patients: Results From the UNITI/IM-UNITI Trials

S733 Impact of Inflammatory Burden on Efficacy of Upadacitinib Maintenance Therapy in Ulcerative Colitis: Results From the Phase 3 U-ACHIEVE Study

Introduction: Upadacitinib (UPA) has demonstrated superior efficacy to placebo (PBO) and a favorable safety profile in patients with moderately to severely active ulcerative colitis (UC) in trial U-ACHIEVE Maintenance, in which two maintenance doses of UPA (30mg and 15mg once daily [QD]) were evaluated.1–3 However, data are limited on the impact of inflammatory burden on the efficacy of the two maintenance doses. Methods: The primary efficacy analysis of U-ACHIEVE Maintenance included the first 451 patients who achieved a clinical response (per Adapted Mayo score) after 8 weeks of UPA 45mg QD treatment in the induction trials. The primary endpoint was clinical remission per Adapted Mayo score at Week 52 and a key secondary endpoint was endoscopic improvement at Week 52. This post hoc analysis evaluated the efficacy, based on these endpoints, of UPA 30mg vs UPA 15mg maintenance therapy in patients in U-ACHIEVE Maintenance stratified by three measures of inflammatory burden: baseline Full Mayo score >9 vs ≤9, presence of pancolitis (yes vs no), and presence of ≥1 extraintestinal manifestation (yes vs no). Results: Overall, 451 patients (PBO: n=149, UPA 15mg: n=148, and UPA 30mg: n=154) were included in the intent-to-treat maintenance population. Both UPA 30mg and UPA 15mg demonstrated favorable efficacy compared with PBO, regardless of the inflammatory burden (Table). However, the differences in proportions of responders who achieved clinical remission at Week 52 and who received UPA 30mg vs UPA 15mg were greater in patients with a high inflammatory burden (difference range: 12.0–22.0%) than those patients without a high inflammatory burden (difference range: 1.4–6.2%; Table). Similar results were seen for proportions of patients who achieved endoscopic improvement at Week 52 (high inflammatory burden [difference range: 12.0–26.1%] relative to those without high inflammatory burden [difference range: 0.2–14.1%]). Conclusion: Both UPA maintenance doses were efficacious compared with PBO, regardless of inflammatory burden, in the achievement of clinical remission and endoscopic improvement. Although results should be interpreted with respect to the small sample size in some subgroups and the post hoc nature of the analysis, these data suggest that patients with a high inflammatory burden of UC may have a relatively greater benefit from UPA 30mg than UPA 15mg, compared with those without high inflammatory burden. Table 1. - PBO, n/N (%)(N=149) UPA 15 mg QD, n/N (%)(N=148) UPA 30 mg QD, n/N (%)(N=154) Difference between UPA 30 mg vs UPA 15 mg a , % Primary endpoint: Clinical remission b at Week 52 per Adapted Mayo Score BL Full Mayo score ≤9 BL Full Mayo score >9 7/74 (9.5)11/75 (14.8) 40/75 (53.1)23/73 (31.2) 40/73 (54.5)40/79 (50.4) 1.419.2 Pancolitis at BL, noPancolitis at BL, yes 13/79 (16.5)5/70 (7.1) 31/66 (46.6)32/82 (38.8) 36/68 (52.8)44/86 (50.8) 6.212.0 EIM at BL, noEIM at BL, yes 13/112 (11.6)5/37 (13.7) 50/112 (44.3)13/36 (36.1) 56/113 (49.4)24/41 (58.1) 5.122.0 Key secondary endpoint: Endoscopic improvement c at Week 52 BL Full Mayo score ≤9BL Full Mayo score >9 8/74 (10.8)14/75 (18.1) 45/75 (60.4)27/73 (36.7) 44/73 (60.6)50/79 (62.8) 0.226.1 Pancolitis at BL, noPancolitis at BL, yes 16/79 (20.3)6/70 (8.0) 33/66 (49.6)39/82 (47.9) 43/68 (63.7)52/86 (59.9) 14.112.0 EIM at BL, noEIM at BL, yes 15/112 (13.7)6/37 (16.9) 57/112 (50.9)15/36 (41.7) 68/113 (60.2)27/41 (65.4) 9.323.7 Data are from the ITT population, defined as the first 450 randomized and treated patients with 8-week UPA 45 mg QD induction treatment who were enrolled in Cohort 1 under the protocol for the 52-week maintenance treatment period. The actual number of patients in the analysis was 451 due to the same enrollment date of the 450th and 451st patients. Non-responder imputation incorporating multiple imputations was performed to handle missing data due to COVID-19 incidence.aNot part of the predefined statistical analyses.bAdapted Mayo score ≤2, with stool frequency subscore ≤1 (and not greater than induction baseline), rectal bleeding subscore of 0, and endoscopic subscore ≤1.cEndoscopic subscore ≤1.BL, baseline; EIM, extraintestinal manifestation; ITT, intent-to-treat; PBO, placebo; QD, once daily; UPA, upadacitinib.

S2725 Enteral Nutrition in Crohns Disease With Abscess

Introduction: Enteral nutrition has emerged as a treatment option for patients with active Crohn’s disease. We report a patient achieving remission with enteral nutrition in conjunction with ustekinumab. Case Description/Methods: A 29-year-old Caucasian male with Crohn’s disease not on therapy presented with abdominal pain, nausea and vomiting. In the past 3 years, he had multiple visits to urgent care for symptoms, each treated with systemic steroids. On presentation, he had an elevated CRP of 143.9 mg/L and MR enterography showed inflammation in the small bowel and terminal ileum. The patient completed a 7-day course of piperacillin-tazobactam and was started on ustekinumab. He was readmitted 10 days later with WBC of 16.9 10*3/ul, CRP of 305.6 mg/L, tachycardia, night sweats and worsening abdominal pain. Imaging showed continued inflammation of small bowel and terminal ileum with a mesenteric abscess connected to the D4 portion of duodenum by a fistulous tract. Piperacillin-tazobactam was started for 14 days along with 5 weeks of exclusive enteral nutrition (EEN) with BOOST, ∼2145 kcals daily. Repeat imaging showed interval decrease in abscess size and then complete resolution. Disease remission was obtained with alleviation of abdominal pain and weight gain of 5 lbs. Labs normalized with CRP < 3 mg/L, at the end of the 5 weeks of EEN. Discussion: EEN is the administration of a polymeric formula as the sole source of nutrition for a limited period (4-8 weeks). In Crohn’s disease, EEN has been shown to help reach remission in 85-90% of patients. It has special consideration in achieving remission in CD patients who have steroid intolerance or contraindications to systemic steroids. The mechanism of EEN in treatment of Crohns disease is not completely understood but is hypothesized to be multifactorial and potentially involve alterations in gut microbiota, decreasing gut permeability, and allowing restoration of epithelial barrier. Limited studies have been conducted on concomitant use of EEN with biologic agents. These studies have primarily been done looking at anti-TNF agents, such as infliximab, and sustained remission rates. Induction therapy with such agents as ustekinumab take time to have clinical effect, 56% of patients have response in 6 weeks. In this patient, initiation of ustekinumab along with EEN was successful in achievement of clinical remission and reduction in inflammatory markers.

Serum leucine-rich alpha-2 glycoprotein as a predictive factor of endoscopic remission in Crohn's disease.

The usefulness of fecal calprotectin (FC) and serum leucine-rich alpha-2 glycoprotein (LRG) assessing the activity of Crohn's disease (CD) remains to be fully demonstrated in Asia. The present study aimed to elucidate whether FC and LRG could predict endoscopic remission (ER) in Japanese patients with CD. Between October 2018 and July 2021, we prospectively observed treatment courses of CD patients treated with biologic agents. The optimal cutoff values of Crohn's Disease Activity Index (CDAI), serum C-reactive protein (CRP), serum albumin (Alb), FC, and LRG levels for predicting ER at week 52 were calculated using receiver operating characteristic (ROC) curves. We also analyzed the correlations between the achievement of clinical remission (CR) or biomarker remission (BR) at week 12/24/52 and ER at week 52. Among 53 patients who completed 52weeks of observation, 20 (37.7%) achieved ER at week 52. Using the calculated cutoff values, patients who achieved CR (CDAI≤112) or BR (CRP≤0.42mg/dL, Alb≥3.8g/dL, FC≤287μg/g, or LRG≤13.6μg/mL) at week 12/24/52 had a higher ER rate at week 52. FC-BR at week 12/24 showed low sensitivity (0.58/0.60)but high specificity (0.78/0.74)for predicting ER; LRG-BR at week 12/24 also showed low sensitivity (0.68/0.74) but high specificity (0.87/0.78). However, FC-BR and LRG-BR at week 52 had improved sensitivity (0.80/0.84) while specificity remained (0.79/0.85). From the early phase of biologic treatment, both FC and LRG had high specificity for predicting ER at week 52. LRG showed higher sensitivity than FC.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

P722 Compositional differences of gut microbiome using taxonomic profiling in patients with ulcerative colitis after treatment with vedolizumab

Abstract Background Gut microbial dysbiosis has been suggested to contribute to pathogenesis of inflammatory bowel disease (IBD). Vedolizumab (VDZ), an α4β7 integrin blocker, has been used as an effective agent for patients with IBD. However, effect of VDZ on gut microbiome and its relationship with efficacy outcomes are still unclear. We investigated gut microbial change in patients with ulcerative colitis (UC) during VDZ treatment. Methods Patients with UC were prospectively enrolled and were given a 300 mg infusion of VDZ at weeks 0, 2, and 6 as an induction therapy and then every 8 weeks as a maintenance therapy. In cases of insufficient response, the interval of maintenance therapy was shortened to every 4 week infusion. Faecal samples were collected at weeks 0, 14, and 54 and 16S rRNA gene microbiome profiling analysis was performed. Clinical remission (CREM), clinical response (CRES), endoscopic mucosal healing (MH) and biochemical response (BioRES) were evaluated. Compositional differences in microbiome were analysed according to CREM, CRES, MH, and BioRES at weeks 0, 14, and 54. Results Faecal samples were collected from 27 patients and patients were classified according to their outcomes (Table 1). In the analyses regarding species richness (ACE, Chao1, Jackknife, The number of OTUs) and diversity indices (NPShannon, Shannon, Simpson, Phylogenetic Diversity), no significant difference was observed among groups at weeks 0, 14, and 54. There were no significant changes in microbial composition at week 14 and 54, respectively compared to basal level. However, compared to baseline, relative abundance of genus Prevotella showed significant differences between groups which achieved normalsation of C-reactive protein or not (p=0.0394) (Figure 1). In the linear discriminant analysis effect size (LEfSe) analysis, the genus Actinomyces and the species Actinomyces odontolyticus group increased in patients who had no response at efficacy outcomes (achievement of clinical remission, achievement of clinical response, achievement of endoscopic mucosal healing, normalisation of C-reactive protein, and normalisation of faecal calprotectin) at week 14, compared to week 0 (Fig 2A). The genus Clostridium_g24, the species Paraprevotella_uc and PAC001224_s were also significantly increased in the same patient group at week 54 (Fig 2B). Conclusion In UC patients treated with VDZ, microbial composition showed differences depending on the achievement of efficacy outcomes. Further studies regarding the causal relationship between microbial composition and outcomes are warranted with a larger number of patients.

P324 Tacrolimus for induction of remission in refractory ulcerative colitis: a Cochrane systematic review

Abstract Background There is a limited number of treatment options for patients with corticosteroid refractory ulcerative colitis (UC). We aimed to evaluate tacrolimus for induction of remission in these patients. Methods MEDLINE, Embase, CENTRAL, Clinicaltrials.gov and ICTRP were searched up to October, 2021 to identify all relevant randomised contolled trials (RCTs). The authors independently reviewed potentially relevant studies to determine eligibility based on pre-specified criteria. A data extraction form was developed and used to extract data from included studies. Data were analysed using Review Manager. The primary outcomes were induction of remission and clinical improvement, as defined by the studies. Results Five RCTs were included with a total of, 347 participants with active UC. There is low certainty (oral and rectal) tacrolimus may be superior for clinical remission when compared to placebo (14/87 to, 1/61, RR, 3.76, 95% CI, 1.03 to, 13.73). There is low certainty (oral and rectal) tacrolimus may be superior for clinical improvement when compared to placebo (45/87 to, 7/61, RR, 4.47, 95% CI, 2.15 to, 9.29. The results on adverse events are of very low certainty and no conclusions can be drawn. There is low certainty there may be no difference in achievement of clinical remission when tacrolimus suppositories (16/44) were compared to beclomethasone (15/44) (RR, 1.07, 95% CI, 0.60 to, 1.88). There is low certainty there may be no difference in clinical improvement when tacrolimus suppositories (22/44) were compared to beclomethasone (22/44) (RR, 1.00, 95% CI, 0.66 to, 1.88). There is low cerainty there may be no difference in serious adverse events when tacrolimus suppositories (1/44) were compared to placebo suppositories (0/44) (RR, 1.00, 95% CI, 0.13 to, 71.70) and total adverse events (21/44 to, 14/44) (RR, 1.50, 95% CI, 0.88 to, 2.55). The evidence on the efficacy and safety of tacrolimus compared to cyclosporine is of very low quality and no conclusions can be drawn. Conclusion The cohorts studied are small, with missing data sets, short follow-up, and the clinical endpoints used are not in line with those suggested by regulatory bodies. No clinical practice conclusions can be made.This review highlights the need for further research that targets relevant clinical questions, uses appropriate trial methodology, and reports key findings in a systematic manner that facilitates future integration of findings with current evidence to better inform clinicians and patients. Future studies need to be adequately powered and of pertinent duration to capture the effectiveness of tacrolimus in the medium-to-long term. Well-structured efficacy studies need to be followed up by long-term phase, 4 extensions to provide key outputs and inform a real-world setting.

Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus

BackgroundIntravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied.AimTo determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis.MethodsEighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks.ResultsResponse rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus.ConclusionsPatients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.