P016 Impact of Non-Remission on Health-Related Quality of Life and Patient Reported Outcomes in Patients With Crohn's Disease: Targeted Literature Review.

BACKGROUND: Crohn's disease (CD) leads to chronic inflammation of the gastrointestinal tract that significantly impacts patients over an entire lifetime. The decrease in health-related quality of life (HRQoL) may have an impact on patient's level of functioning, work productivity, and other activities. The goal of treatment for CD is clinical remission based on clinical, endoscopic, and biological parameters. There has been introduction of new treatments in recent years. A review was conducted to assess the impact of non-remission on HRQoL and patient reported outcomes (PROs) in patients with CD. METHODS: Literature search of English language publications from 2015-2021 was conducted in Embase® and MEDLINE®. Real world studies meeting predefined criteria (adult CD patients in non-remission presenting data for HRQoL or PROs) were included in the review. Data on study characteristics, disease characteristics, HRQoL and PROs were extracted from the included studies. RESULTS: The review retrieved 1384 records from which only 10 studies presented data for HRQoL and/or PROs. The definition of remission varied across the included studies. In most studies (90%), remission was defined using Harvey-Bradshaw Index and/or Crohn's disease activity index. Different tools were used to assess HRQoL and sleep quality. In a study, no normalization of long-term HRQoL was observed in patients who did not achieve clinical remission. A negative correlation was found between utility indexes & disease activity in a study (ρ = -0.586, p < 0.001). A significant correlation was also observed in a study between HRQoL and disease activity where HRQoL in patients with active disease was poor compared to patients in remission. The HRQoL domains of anxiety, depression and pain were impacted in non-remitters. The mean IBDQ score was 189 ± 16.1 in remitters and 145 ± 15.9 in non-remitters (p < 0.001). A strong negative correlation between IBDQ and disease activity was reported by a study. In a study, work productivity was moderately but significantly correlated with disease activity indicating reduction in work productivity of patients with active disease (mild, moderate, and severe) compared to remitters. In another study, severe disease activity was significantly associated with an increased amount of fragmented sleep. Patients with moderate to severe disease had a significantly longer time awake after falling asleep compared to patients in remission or with mild disease activity (65.8 minutes, 44.3 minutes, 49.1 minutes, respectively). Patients with active disease also reported poor sleep quality and suffered from excessive daytime sleepiness. There was a significant difference in the median sleep efficiency for patients with moderate to severe disease compared to patients with remission. CONCLUSION: This targeted review found in general that not being able to achieve/maintain remission had an impact on the HRQoL of patients with CD. Patients not achieving remission were associated with decreased work productivity, poor sleep quality, lower sleep efficiency, daytime sleepiness and poor HRQoL. However, studies assessing HRQoL and PROs in the real-world are scarce, with discrepancies based on remission status. Further research is warranted, and health care providers and payers should consider the impact of therapies on the improvement in HRQoL of patients with CD.

P025 The Impact of Non-Remission on Costs and Resource Use In Patients With Crohn's Disease: Targeted Literature Review.

BACKGROUND: The incidence of Crohn's disease (CD) has been rising globally. Patients with CD are at an increased risk of mortality compared to general population. The goal of treatment for CD is clinical remission based on clinical, endoscopic, and biological parameters. There has been introduction of new treatments in recent years. A review was conducted to assess the impact of non-remission on cost and resource use in patients with CD. METHODS: Literature search of English language publications from 2015-2021 was conducted in Embase® and MEDLINE®. Real world studies meeting predefined review criteria were included and data were extracted in pre-defined extraction form. RESULTS: The review retrieved 1384 records; 24 fulfilled eligibility criteria. The definition of remission varied across the included studies. In most studies (66.67%), remission was defined using Crohn's disease activity index and/or Harvey-Bradshaw Index. Among included evidence, 21 studies reported proportion of non-remitters undergoing surgery, 11 studies reported the data for hospitalizations and 2 studies reported cost of treatment for non-remitters. Proportion of non-remitters requiring hospitalizations ranged from 6.7% to 30.6%. Univariate analysis suggested that deep remission was significantly associated with lower hazards for being hospitalized (HR: 0.18 [95%CI: 0.08, 0.25]); suggesting a significantly higher risk of hospitalization in non-remitters. In a study, the mean duration of cumulative hospital stays was significantly higher in patients with a pathological MRI (19.7 ± 7.4 days) compared to patients in deep remission (0.75 ± 0.52 days, p < 0.05). The proportion of non-remitters undergoing surgery ranged from 1.5% to 57%. The proportion of patients undergoing surgery were high in non-remitters compared to remitters. Hematopoietic stem cell transplantation was needed in 4.1% non-remitters and repeat surgery in 3.5% non-remitters. In a study, surgery was required by 11.6% patients with no healing (due to refractory strictures, penetrating complications, and severe refractory disease) and 11.5% patients presenting with mucosal healing (due to structuring and penetrating complications), while no patient with transmural healing required surgery. Non-remission led to higher total costs, especially in patients undergoing surgery or dependent on in-hospital administrated drugs. The costs were 4 to 6 times higher in patients in an active period and 19 times higher for patients requiring surgery compared to patients in remission. Adjusted total indirect cost among participants with disease remission was reduced by 60% compared to patients with active disease (€243.44 per patient per month, p < 0.001). The number of consultations in the last month, monthly consultation cost, current treatment cost, amount of benefits from public organisations, and self-reported expenses on all categories were significantly higher in non-remitters compared to patients in remission. CONCLUSION: This targeted review found in general that not being able to achieve/maintain remission has an impact on the economic outcomes of patients with CD. Non-remission in patients with CD was associated with an increased number of hospitalizations and surgeries. The cost of treatment for non-remitters was significantly higher than patients in remission. None of the studies presented data for patients who respond to treatment but are not able to achieve remission. Further research is warranted in these patients.

The economic impact of suboptimal treatment and treatment switch among patients with Crohn's disease treated with a first-line biologic - A US retrospective claims database study.

AIMS: Suboptimal treatment indicators, including treatment switch, are common among patients with Crohn's disease (CD), but little is known about their associated healthcare resource utilization (HRU) and costs. This study assessed the impact of suboptimal treatment indicators on HRU and costs among adults with CD newly treated with a first-line biologic. METHODS: Adult patients with CD were identified in the IBM MarketScan Commercial Subset (10/01/2015-03/31/2020). The index date was defined as initiation of the first-line biologic, and the study period was defined as the 12 months following the index date. Patients were classified into Suboptimal Treatment and Optimal Treatment cohorts based on observed indicators of suboptimal treatment during the study period. Patients in the Suboptimal Treatment Cohort with a treatment switch were classified into the Treatment Switch Cohort and compared to patients with no treatment switch. All-cause HRU and costs were measured during the study period and assessed for patients with suboptimal vs optimal treatment and patients with vs without a treatment switch. RESULTS: The study included 4,006 patients (Suboptimal Treatment: 2,091, Optimal Treatment: 1,915). Treatment switch was a common indicator of suboptimal treatment (Treatment Switch: 640, No Treatment Switch: 3,366). HRU and costs were significantly higher among patients with suboptimal treatment than those with optimal treatment (annual costs: $92,043 vs $73,764; p < 0.01), and among those with a treatment switch than those with no treatment switch (annual costs: $95,689 vs $81,027; p < 0.01). Increases in the number of suboptimal treatment indicators were associated with increased costs. LIMITATIONS: Claims data were used to identify suboptimal treatment indicators based on observed treatment patterns; reasons for treatment decisions could not be assessed. CONCLUSION: This study demonstrates that patients with suboptimal treatment indicators, including treatment switch, incur substantially higher HRU and costs compared to patients receiving optimal treatment and those that do not switch treatments.

Efficacy of ustekinumab vs. advanced therapies for the treatment of moderately to severely active ulcerative colitis: a systematic review and network meta-analysis.

Objective: To compare the relative efficacy of ustekinumab (UST) vs. other therapies for 1-year response and remission rates in patients with moderate-severe UC.Methods: Randomized controlled trials reporting induction and maintenance efficacy of anti-TNFs (infliximab [IFX], adalimumab [ADA], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOF) or UST were identified through a systematic literature review (SLR). Analyses were conducted for clinical response, clinical remission and endoscopic-mucosal healing for populations with and without failure of prior biologics (non-biologic failure [NBF]; biologic failure [BF]). Maintenance data from trials with re-randomized response designs were re-calculated to correspond to treat-through arms. Bayesian network meta-analyses (NMA) were conducted to obtain posterior distribution probabilities for UST to perform better than comparators.Results: Six trials included NBF patients and four included BF patients. In NBF patients, UST as a 1-year regimen showed higher probabilities of clinical response, remission and endoscopic-mucosal healing vs. all treatments: Bayesian probabilities of UST being better than active therapies ranged from 91% (VDZ) to 100% (ADA) for response; 82% (VDZ) to 99% (ADA) for remission and 82% (IFX) to 100% (ADA and GOL) for endoscopic-mucosal healing. In BF patients, UST was the most effective treatment (Q8W dose); however, effect sizes were smaller than in the NBF population.Conclusions: Results indicate a higher likelihood of response, remission and endoscopic-mucosal healing at 1 year with UST vs. comparators in the NBF population. In BF patients, a higher likelihood of response to UST vs. the most comparators was also observed, although results were more uncertain.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation.

OBJECTIVE: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada). METHODS: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs). RESULTS: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY. LIMITATIONS: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze. CONCLUSION: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000-$100,000 per QALY.

Elucidation of the epitope of a latency-inducing antibody: identification of a new molecular target for PAI-1 inhibition.

The monoclonal antibody MA-33B8, directed against the serpin plasminogen activator inhibitor-1 (PAI-1), has unique functional properties as it induces acceleration of the active-to-latent transition (Verhamme I et al. J Biol Chem 274: 17511-7, 1999), resulting in PAI-1 activity neutralization. In this study, we have identified Lys(88), Asp(89), Lys(176) and His(229) as the major residues of the conformational epitope. Lysine(88) and aspartic acid(89), contributing the most, are located on the loop between alpha-helix D and beta-strand 2A. Strikingly, these residues undergo dramatic conformational changes during latency conversion. The three dimensional localization of this epitope and its differential exposure in active and latent forms of PAI-1 provide a molecular explanation for the underlying mechanism of MA-33B8. Rearrangements of hydrogen bonds in this region upon latency transition, strongly suggest that binding of MA-33B8 may result in the generation of energy required in the rate-limiting step of latency transition. Thus, this novel epitope reveals a new interaction site in PAI-1 as a putative molecular target to modulate PAI-1 activity.

Biochemical importance of glycosylation of plasminogen activator inhibitor-1.

The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous glycosylation pattern of the sites at N209 and N265, while that at N329 is not utilised. The IC(50)-values for inactivation of PAI-1 by 4 monoclonal antibodies differed strongly between glycosylated PAI-1 and non-glycosylated PAI-1 expressed in E. coli. For 3 antibodies, an overlap of the epitopes with the glycosylation sites could be excluded as explanation for the differential reactivity. The latency transition of non-glycosylated, but not of glycosylated PAI-1, was strongly accelerated by a non-ionic detergent. The different biochemical properties of glycosylated and non-glycosylated PAI-1 depended specifically on glycosylation of either one or the other of the utilised sites. The PAI-1-binding protein vitronectin reversed the changes associated with the lack of glycosylation at one of the sites. Our results stress the importance of the source of PAI-1 when studying the mechanisms of action of PAI-1-inactivating compounds of potential clinical importance.