Panés, Julián

Abstract Background Small bowel fibrostenotic strictures are common in patients with Crohn’s disease (CD). No global consensus recommendations on definitions, diagnosis and clinical management are available. Methods Several systematic reviews followed by a RAND/University of California Los Angeles appropriateness study on the definitions, diagnosis and clinical management of fibrostenosing CD in clinical practice were performed. A panel of 28 global experts and a patient representative were convened. They assessed a total of 152 candidate items. The items were subsequently evaluated for appropriateness. Results No accurate predictive biomarkers are available for naïve or anastomotic fibrostenosing strictures. Accurate diagnosis of fibrostenosing CD requires cross-sectional imaging which should evaluate bowel wall thickness, luminal narrowing and prestenotic dilatation. A potential inflammatory component should be assessed. Abdominal cross-sectional imaging was considered necessary prior to any treatment decision. The panel proposed an approach to medical, endoscopic, and surgical therapies (Figure 1 and Table 1). Technical characteristics for endoscopic balloon dilation and follow up strategies after successful dilation therapy were identified. Appropriateness, types and performance of different surgical approaches in various settings were evaluated. Conclusion This global consensus provides clinical guidance for the diagnostic and therapeutic management of patients with fibrostenotic CD.

Abstract Background Patients with Crohn’s disease (CD) experience reduced quality of life (QoL), and disease-related impact on work productivity, contributing to a high disease burden. This study evaluated the association of achieving endoscopic outcomes at week 12 and associated QoL at week 52 in patients with CD treated with upadacitinib (UPA). Methods This post-hoc analysis evaluated data from two Phase 3 UPA induction (U-EXCEED and U-EXCEL) trials and one maintenance (U-ENDURE) trial in patients with moderate to severe CD. Patients who responded to 12-week induction therapy with UPA (45 mg per day [QD]) in U-EXCEED or U-EXCEL and received maintenance therapy with UPA (15 or 30 mg QD) up to 52 weeks in U-ENDURE were included. Meaningful improvement in QoL outcomes (Inflammatory Bowel Disease Questionnaire [IBDQ] remission ≥170, IBDQ response increase ≥16, Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] response increase ≥9, Short Form 36 [SF-36] Physical Component Score [PCS] and Mental Component Score [MCS] change ≥5, and Work Productivity and Activity Impairment Questionnaire [WPAI] change ≥7%) was evaluated at week 52 and compared between patients who achieved endoscopic response, endoscopic remission and ulcer-free endoscopy (absence of ulceration) at week 12 and those who did not using Chi-square test. Results Of 337 clinical responders included in the analyses, 152 (45.1%), 87 (25.8%), and 75 (22.2%) patients achieved endoscopic response, endoscopic remission, and ulcer-free endoscopy, respectively, at the end of induction. Significantly more patients who achieved an endoscopic response at end of induction (vs those who did not) attained a meaningful improvement in PROs by week 52 (IBDQ remission, 52.6% vs 30.3%; IBDQ response, 56.6% vs 36.8%; FACIT-F response, 46.7% vs 25.9%; SF-36 PCS 49.3% vs 30.8% and MCS 39.5% vs 25.9%; all P≤0.01, Table 1). Additionally, patients who achieved endoscopic response (vs those who did not) at the end of induction were more likely to attain meaningful improvement in WPAI overall work impairment by week 52 (47.1% vs 26.5%, P≤0.01, Table 1). Similar findings were observed in patients who achieved endoscopic remission (P≤0.01, Table 1) and ulcer-free endoscopy (P≤0.05, Table 1) vs those who did not at end of induction. Conclusion Achieving endoscopic outcomes at end of induction treatment was associated with meaningful improvement in quality of life and overall work productivity at 52 weeks for patients with CD receiving UPA. Endoscopic remission and ulcer-free endoscopy were associated with very similar long-term benefit.

Abstract Background We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes. Methods Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks. The percentages of patients reporting a clinically meaningful within-person change from baseline in the Ulcerative Colitis Symptoms Questionnaire, Inflammatory Bowel Disease Questionnaire, Work Productivity and Impairment Questionnaire, 36-Item Short Form Survey, and European Quality of Life-5 Dimension 5 Levels were evaluated at weeks 2 and 8 of induction and at weeks 0 and 52 of maintenance. Results Significant improvements from baseline in all HRQoL measures except the Work Productivity and Impairment Questionnaire–absenteeism were achieved with UPA (P < .001) vs placebo as early as week 2 of induction. These improvements were sustained at week 52 with significantly more patients treated with either 15 mg or 30 mg UPA vs placebo achieving meaningful within-person change in the Ulcerative Colitis Symptoms Questionnaire; Inflammatory Bowel Disease Questionnaire; overall work impairment, presenteeism, and activity impairment; both 36-Item Short Form Survey Physical and Mental Component Summaries; and European Quality of Life-5 Dimension 5 Levels (P < .001). Conclusions Induction treatment with UPA 45 mg significantly improved HRQoL measures. A significantly higher percentage of patients who responded to induction treatment with UPA maintained clinically meaningful improvements consistently across a wide range of HRQoL outcomes after 52 weeks of maintenance therapy with UPA (15 mg and 30 mg) compared with placebo. (ClinicalTrials.gov, Numbers: NCT02819635, NCT03653026).

SummaryBackgroundCrohn's disease has a substantial negative impact on health‐related quality of life (HRQoL).AimTo examine the effects of risankizumab on HRQoL in Crohn's diseaseMethodsWe analysed data from patients with Crohn's disease from 12‐week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52‐week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F), 36‐item Short Form Health Survey (SF‐36), EuroQol 5‐Dimension‐5‐Level (EQ‐5D‐5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52.ResultsAt week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT‐F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p < 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF‐36 physical and mental component summary scores, EQ‐5D‐5L and activity impairment within work productivity measures.ConclusionsRisankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease‐specific and general patient‐reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

Abstract Background Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials. Aims Evaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials. Methods The primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI). Results Baseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p&lt;0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%). Conclusions In patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed. Funding Agencies AbbVie

Abstract Background Darvadstrocel (DVS) is a suspension of expanded allogeneic adipose-derived mesenchymal (stromal) stem cells approved for the treatment of complex Crohn’s perianal fistulas (complex CPF). The INSPIRE (EUPAS24267) registry is a European observational, post-approval study designed to evaluate the real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months after DVS administration. Here we report clinical and safety outcomes from the first interim analysis at 6 months post treatment. Methods Patients with complex CPF treated with DVS according to local standard practice were eligible to enrol. Primary outcomes were clinical response (defined as closure despite gentle finger compression of ≥50% of external openings treated with DVS that were draining at baseline) and clinical remission (defined as closure despite gentle finger compression of all external openings treated with DVS that were draining at baseline). Outcomes were evaluated in the All Treated (AT) and Treated Per Protocol (PP) cohorts (Table 1) 6 months post treatment in patients who had received a single administration of DVS. The number and nature of adverse events (AEs), serious AEs (SAEs) are reported for the AT cohort. Results As of September 2021, 230 patients had enrolled, 225 met the inclusion criteria and 205 had complete treatment data and comprised the AT cohort, of these, 176 were treated per protocol. A total of 138 (AT) and 120 (PP) patients were 6 months post treatment, 66% (92/138) and 58% (69/120) had a 6-month visit, of which, 85% (78/92) and 100% (69/69) had evaluable data at Month 6, respectively. Baseline demographics and clinical and fistula characteristics are shown in Tables 1 and 2. In the AT and PP cohorts, respectively, 73% (57/78) and 74% (51/69) of patients had a clinical response, and 65% (51/78) and 65% (45/69) had clinical remission. Changes in Crohn’s disease (CD) activity (assessed with the Harvey–Bradshaw Index) post treatment were minimal, and most patients had no change in CD activity from baseline. In the AT cohort, 20% (41/205) of patients had ≥1 AE and 9.3% (19/205) had ≥1 SAE. There were no reports of ectopic tissue formation and no deaths. Conclusion This is the first real-world, multi-centre study reporting the effectiveness and safety data after DVS treatment for complex CPF. These interim analysis data are consistent with the pivotal ADMIRE-CD study in terms of effectiveness and safety. The ongoing status of the registry and small number of evaluable patients mean these data should be interpreted with caution, pending future analyses in larger numbers of patients with longer follow-up times.

Abstract Background Health-related quality of life (HRQOL) is reduced in patients (pts) with ulcerative colitis (UC). We report on the HRQOL benefits of maintenance treatment with upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, in pts with moderately to severely active UC in the Phase, 3 multicentre, randomised, double-blind U-ACHIEVE maintenance study (NCT02819635). Methods This study included a primary analysis of, 451 pts who achieved clinical response following treatment with UPA, 45 mg once daily (QD) in two replicate, 8-week induction studies, U-ACHIEVE induction, and U-ACCOMPLISH (NCT03653026). In U-ACHIEVE maintenance, pts from both induction studies were re-randomised, 1:1:1 to receive QD UPA, 15 mg, UPA, 30 mg, or PBO. HRQOL outcomes evaluated included the percent of pts reporting a clinically meaningful within-person change (MWPC) from induction baseline to Week, 0 (maintenance baseline) and Week, 52 (end of maintenance) in a broad range of HRQOL measures, including Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity and Impairment Questionnaire (WPAI), Short Form, 36 (SF-36), European Quality of Life-5 Dimensions, 5 Levels (EQ-5D-5L), and Ulcerative Colitis Symptoms Questionnaire (UC-SQ). Results A total of, 149, 148, and, 154 pts received PBO, UPA, 15 mg, and UPA, 30 mg QD, respectively, during maintenance. At Week, 0 of the maintenance study, there were no significant differences between UPA and PBO treatment groups in the percentage of pts reporting MWPC relative to induction baseline for most pt-reported outcomes (PROs) as all pts enrolled in maintenance were UPA clinical responders during IP. For IBDQ, a significantly greater proportion of pts achieved MWPC criteria (p&lt;0.001) with UPA, 15 mg (68.9%) and UPA, 30 mg (78.6%) vs, 39.6% for PBO at Week, 52 (Figure, 1). Also, a significantly greater proportion of pts treated with either, 15 mg or, 30 mg UPA dosage vs PBO over, 52 weeks achieved MWPC for the WPAI domains (p≤0.01) of overall work improvement, presenteeism, and activity impairment (Figure, 2), in both physical and mental component summaries of SF-36 (p&lt;0.001, Figure, 3), in EQ-5D-5L (p&lt;0.001, Figure, 4), and in UC-SQ (p&lt;0.001). A numerically greater proportion of pts receiving UPA, 30 mg vs, 15 mg achieved MWPC in most PROs at Week 52. Conclusion A significantly higher percentage of pts with moderately to severely active UC who responded to UPA induction therapy maintained clinically meaningful improvements with UPA, 15 mg of, 30 mg compared to PBO consistently across a broad range of HRQOL outcomes after, 52 weeks of maintenance treatment. These HRQOL aspects include IBD symptoms (IBDQ, UC-SQ), work productivity (WPAI), physical and mental functioning (SF-36), and general well-being (IBDQ, EQ-5D).

SummaryBackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present final data from OCTAVE Open, an open‐label, long‐term extension study.AimsThe primary objective of OCTAVE Open was to assess the safety and tolerability of long‐term tofacitinib in patients with ulcerative colitis; evaluating efficacy was a secondary objective.MethodsEligible patients included OCTAVE Induction 1&2 non‐responders and OCTAVE Sustain completers/treatment failures. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. Incidence rates (unique patients with events/100 patient‐years) for adverse events of special interest were calculated; ≤7.0 years of observation. Efficacy endpoints derived from Mayo score were reported ≤36 months (last scheduled endoscopy visit).ResultsIn OCTAVE Open, 769 of 944 patients (81.5%) initially received tofacitinib 10 mg b.d. Among all patients (2440.8 patient‐years of exposure), incidence rates (IRs; 95% confidence intervals) for deaths and adverse events of special interest were: deaths, 0.25 (0.09‐0.54); serious infections, 1.61 (1.14‐2.20); herpes zoster (non‐serious and serious), 3.16 (2.47‐3.97); opportunistic infections, 0.87 (0.54‐1.33); major adverse cardiovascular events, 0.16 (0.04‐0.42); malignancies (excluding non‐melanoma skin cancer), 1.03 (0.67‐1.52); non‐melanoma skin cancer, 0.75 (0.45‐1.19); deep vein thrombosis, 0.04 (0.00‐0.23); pulmonary embolism, 0.21 (0.07‐0.48). At Month 36, 66.9% and 40.3% showed clinical response, 64.6% and 37.1% had endoscopic improvement, and 58.9% and 33.7% maintained or achieved remission, with tofacitinib 5 and 10 mg b.d. respectively.ConclusionTofacitinib demonstrated consistent safety up to 7.0 years. Data collected up to Month 36 support long‐term efficacy beyond the 52‐week maintenance study.