The Influence of Subclinical Active Inflammation on IFX Pharmacokinetic Modeling and Disease Progression Assessment: Findings from a Prospective Real-World Study in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. METHODS: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. RESULTS: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. CONCLUSION: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Burden of Disease and Cost of Illness of Inflammatory Bowel Diseases in Portugal.

Background: Inflammatory bowel diseases' (IBD) increasing incidence and prevalence place a heavy health and economic burden on society. Objectives: This study assesses the burden and cost of IBD in Portugal to support the definition of health policies, resource allocation, and patient care. Methods: The burden of disease was expressed using disability-adjusted life years (DALY). Costs were estimated considering the societal perspective, using a prevalence-based model and prices established by law. An expert panel composed of 5 expert Portuguese gastroenterologists and a patient-reported study were conducted to support the cost analysis and fill in information gaps. Results: In Portugal, with a prevalence of 24,069 IBD patients and an incidence of 15/100,000, the burden of disease was estimated at 6,067 DALYs: 507 resulting from premature deaths and 5,560 from disability. Total cost was estimated at EUR 146 million per year, with direct costs representing 59%. Average yearly cost per IBD patient is EUR 6,075, where 60% is related to Crohn's disease and 40% to ulcerative colitis (UC). Conclusion: This study estimates the annual health burden and cost of IBD in Portugal, thus generating information with the intent to raise awareness of the need to advance health policies as well as better clinical and economic decisions in this pathology.

Contexto: A crescente incidência e prevalência das Doenças Inflamatórias Intestinais (DII) representam um pesado fardo para a saúde e economia na sociedade. Objetivos: Este estudo avalia o custo e a carga da DII em Portugal, com o objetivo de suportar a definição de políticas de saúde, alocação de recursos e cuidados com o doente. Métodos: A carga da doença foi calculada utilizando anos de vida ajustados à incapacidade (DALY). Os custos foram estimados tendo em conta a perspetiva da sociedade, utilizando um modelo baseado na prevalência e preços estabelecidos por lei. Foi realizado um painel de peritos, composto por 5 gastroenterologistas portugueses, assim como um estudo de mercado a doentes, de forma a suportar a análise de custos e colmatar lacunas de informação. Resultados: Em Portugal, com uma prevalência de 24,069 doentes e uma incidência de 15/100,000, o peso das DII foi estimado em 6.067 DALYs: 507 dos quais resultantes de mortes prematuras e 5.560 de incapacidade. O custo total foi estimado em 146 milhões de euros por ano, com os custos diretos a representarem 59% do total. O custo médio anual por doente de DII é de 6.075 EUR, onde 60% está relacionado com Doença de Crohn (DC) e 40% com Colite Ulcerosa. Conclusão: Este estudo estima os encargos anuais para a saúde e o custo da DII em Portugal, gerando informação relevante, com o intuito de alertar para a necessidade de uma evolução nas políticas de saúde, assim como como suportar melhores decisões clínicas e económicas nesta patologia.

The Magnitude of Crohn's Disease Direct Costs in Health Care Systems (from Different Perspectives): A Systematic Review.

BACKGROUND: The prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, causing high impact on the quality of life of patients and an increasing burden for health care systems. In this systematic review, we reviewed the literature concerning the direct costs of Crohn's disease (CD) for health care systems from different perspectives: regional, economic, and temporal. METHODS: We searched for original real-world studies examining direct medical health care costs in Crohn's disease. The primary outcome measure was the mean value per patient per year (PPY) of total direct health care costs for CD. Secondary outcomes comprised hospitalization, surgery, CD-related medication (including biologics), and biologics mean costs PPY. RESULTS: A total of 19 articles were selected for inclusion in the systematic review. The studies enrolled 179 056 CD patients in the period between 1997 and 2016. The pooled mean total cost PPY was €6295.28 (95% CI, €4660.55-€8503.41). The pooled mean hospitalization cost PPY for CD patients was €2004.83 (95% CI, €1351.68-€2973.59). The major contributors for the total health expenditure were biologics (€5554.58) and medications (€3096.53), followed by hospitalization (€2004.83) and surgery (€1883.67). No differences were found between regional or economic perspectives, as confidence intervals overlapped. However, total costs were significantly higher after 2010. CONCLUSIONS: Our review highlighted the burden of CD for health care systems from different perspectives (regional, economic, and temporal) and analyzed the impact of the change of IBD treatment paradigm on total costs. Reducing the overall burden can depend on the increase of remission rates to further decrease hospitalizations and surgeries.

Non-biological Complex Drugs (NBCDs): Complex Pharmaceuticals in Need of Individual Robust Clinical Assessment Before Any Therapeutic Equivalence Decision.

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs "follow-on products" approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of "well-established use" applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

Inflammatory Bowel Disease Reoperation Rate Has Decreased Over Time If Corrected by Prevalence.

INTRODUCTION: Despite the recent emergence of expensive biologic therapies, hospitalization and surgery remain important contributors for the overall costs of inflammatory bowel disease (IBD). In this study, we aimed to describe the burden of reoperations in patients with IBD by evaluating reoperation rates, charges, and risk factors over 16 years. METHODS: We performed a retrospective analysis of all hospital discharges, with focus on reoperations and with a primary diagnosis of IBD, in public hospitals between 2000 and 2015 in mainland Portugal from the Central Administration of the Health System's national registry. We collected data on patient, clinical, and healthcare charges. We used multivariate regressions to estimate the risk factors of IBD-related reoperations. RESULTS: We found that 5% of IBD-related hospitalizations were related to reoperations. The number of reoperations per year increased by approximately 200%. However, when corrected by the prevalence of the disease, IBD reoperation rates decreased. Mean IBD-related charges per hospitalization were 7,780 &OV0556; in 2000 and 10,592 &OV0556; in 2015, with total charges reaching 6.7 million euros by the end of the study. Risk factors for reoperation include urgent hospitalization, in patients with ulcerative colitis (odds ratio 1.94, 95% confidence interval 1.19-3.17, P = 0.008), and colic disease, in patients with Crohn's disease (odds ratio 1.57, 95% confidence interval 1.06-2.34, P = 0.025). DISCUSSION: To obtain an accurate scenario of reoperations among patients with IBD, it is mandatory to adjust the number of reoperations to the prevalence of the disease. Reoperation and its risk factors should be closely monitored to decrease the burden of IBD to the healthcare system.

Health-care costs of inflammatory bowel disease in a pan-European, community-based, inception cohort during 5 years of follow-up: a population-based study.

BACKGROUND: Inflammatory bowel disease (IBD) places a significant burden on health-care systems because of its chronicity and need for expensive therapies and surgery. With increasing use of biological therapies, contemporary data on IBD health-care costs are important for those responsible for allocating resources in Europe. To our knowledge, no prospective long-term analysis of the health-care costs of patients with IBD in the era of biologicals has been done in Europe. We aimed to investigate cost profiles of a pan-European, community-based inception cohort during 5 years of follow-up. METHODS: The Epi-IBD cohort is a community-based, prospective inception cohort of unselected patients with IBD diagnosed in 2010 at centres in 20 European countries plus Israel. Incident patients who were diagnosed with IBD according to the Copenhagen Diagnostic Criteria between Jan 1, and Dec 31, 2010, and were aged 15 years or older the time of diagnosis were prospectively included. Data on clinical characteristics and direct costs (investigations and outpatient visits, blood tests, treatments, hospitalisations, and surgeries) were collected prospectively using electronic case-report forms. Patient-level costs incorporated procedures leading to the initial diagnosis of IBD and costs of IBD management during the 5-year follow-up period. Costs incurred by comorbidities and unrelated to IBD were excluded. We grouped direct costs into the following five categories: investigations (including outpatient visits and blood tests), conventional medical treatment, biological therapy, hospitalisation, and surgery. FINDINGS: The study population consisted of 1289 patients with IBD, with 1073 (83%) patients from western Europe and 216 (17%) from eastern Europe. 488 (38%) patients had Crohn's disease, 717 (56%) had ulcerative colitis, and 84 (6%) had IBD unclassified. The mean cost per patient-year during follow-up for patients with IBD was €2609 (SD 7389; median €446 [IQR 164-1849]). The mean cost per patient-year during follow-up was €3542 (8058; median €717 [214-3512]) for patients with Crohn's disease, €2088 (7058; median €408 [133-1161]) for patients with ulcerative colitis, and €1609 (5010; median €415 [92-1228]) for patients with IBD unclassified (p<0·0001). Costs were highest in the first year and then decreased significantly during follow-up. Hospitalisations and diagnostic procedures accounted for more than 50% of costs during the first year. However, in subsequent years there was a steady increase in expenditure on biologicals, which accounted for 73% of costs in Crohn's disease and 48% in ulcerative colitis, in year 5. The mean annual cost per patient-year for biologicals was €866 (SD 3056). The mean yearly costs of biological therapy were higher in patients with Crohn's disease (€1782 [SD 4370]) than in patients with ulcerative colitis (€286 [1427]) or IBD unclassified (€521 [2807]; p<0·0001). INTERPRETATION: Overall direct expenditure on health care decreased over a 5-year follow-up period. This period was characterised by increasing expenditure on biologicals and decreasing expenditure on conventional medical treatments, hospitalisations, and surgeries. In light of the expenditures associated with biological therapy, cost-effective treatment strategies are needed to reduce the economic burden of inflammatory bowel disease. FUNDING: Kirsten og Freddy Johansens Fond and Nordsjællands Hospital Forskningsråd.

Transmural Histological Scoring Systems in Crohn's Disease: A Systematic Review With Assessment of Methodological Quality and Operating Properties.

BACKGROUND: The relative proportion of inflammation and fibrosis in a stricture is highly relevant in defining the clinical approach for Crohn's disease [CD] patients. Whereas transmural inflammation in CD can be accurately estimated by cross-sectional imaging, evaluating the extent and severity of fibrosis still requires surgical pathology of intestinal resection specimens. This study systematically reviewed all existing transmural histopathological scoring systems developed for the assessment of inflammation and/or fibrosis in CD. METHODS: A systematic review of histopathological scoring systems for the assessment of transmural inflammation and/or fibrosis in CD, focusing on originally developed scoring systems. Risk of bias, methodological quality, and operating or psychometric properties [validity, reliability, responsiveness, and feasibility] of each histological scoring system were analysed. RESULTS: A total of 29 original scoring systems were included in this review. Three scoring systems were highlighted as the most widely reproduced, one aimed at assessing inflammation only and two aimed at assessing inflammation and fibrosis. These scores were more widely reproduced probably due to their ease of application in clinical studies. Two highly comprehensive scores were identified, showing good operating properties and high methodological quality, as well as the lowest risk of bias; these should, therefore, be further validated in clinical research studies. CONCLUSIONS: This study reviewed all existing transmural histopathological scoring systems for the assessment of inflammation and/or fibrosis in CD and identified the most reliable and accurate scores for clinical research and clinical practice settings.

Rehospitalization rates, costs, and risk factors for inflammatory bowel disease: a 16-year nationwide study.

AIMS: We aimed to describe the burden of rehospitalization in patients with inflammatory bowel disease (IBD), by evaluating rehospitalization rates, charges, and risk factors over 16 years. METHODS: We performed a retrospective analysis of all hospital discharges with a primary diagnosis of IBD in public hospitals between 2000 and 2015 in mainland Portugal from the Central Administration of the Health System (ACSS)'s national registry. We collected data on patient, clinical, and healthcare charges. We used survival analysis to estimate the rate and risk factors of IBD-related rehospitalization. RESULTS: We found that 33% (n = 15,931) of the IBD-related hospitalizations corresponded to rehospitalizations, which increased by 12% over 16 years. However, IBD rehospitalization rate per 100,000 IBD patients decreased 2.5-fold between 2003 and 2015. Mean IBD-related rehospitalization charges were €14,589/hospitalization-year in 2000 and €17,548 /hospitalization-year in 2015, with total rehospitalization charges reaching €3.1 million/year by 2015. Overall, the 30-day rate of rehospitalization was 24% for Crohn's disease (CD) and 22.4% for ulcerative colitis (UC). Novel risk factors for rehospitalization include penetrating disease in CD patients {hazard ratio (HR) 1.34 [95% confidence interval (CI) 1.20-1.51], p < 0.001} and colostomy in UC patients [HR 2.84 (95% CI 1.06-7.58)]. CONCLUSION: IBD-related rehospitalization should be closely monitored, and efforts to reduce its risk factors should be made to improve the quality of care and, consequently, to reduce the burden of IBD.

Multidisciplinary management of the nocebo effect in biosimilar-treated IBD patients: Results of a workshop from the NOCE-BIO consensus group.

The high cost of biological drugs for patients with inflammatory bowel disease (IBD) considerably impacts on health-care budgets. Since the patent of biological products expired, cheaper biosimilars have entered the market. Available data coming from real-world cohorts and clinical trials indicate that the efficacy and safety of biosimilars is comparable to that of the originator drugs. Treating IBD patients with a biosimilar may be complicated by the risk of the nocebo effect, a negative effect of a pharmacological or non-pharmacological treatment, induced by patients's expectations and unrelated to the physiological action of the treatment. The nocebo effect can negatively affect treatment outcomes and hamper the cost-savings of biosimilars. Reducing the nocebo effect requires a multidisciplinary effort of all health-care providers in charge of biosimilar-treated IBD patients. The aim of the review is to reflect the key messages of an international workshop on this topic, including viewpoints from the perspective of physicians, nurses, psychologists, pharmacists and patients.

Unmet Medical Needs in Ulcerative Colitis: An Expert Group Consensus.

BACKGROUND: The authors aimed to conduct an extensive literature review and consensus meeting to identify unmet needs in ulcerative colitis (UC) and ways to overcome them. UC is a relapsing and remitting inflammatory bowel disease with varied, and changing, incidence rates worldwide. UC has an unpredictable disease course and is associated with a high health economic burden. During 2016 and 2017, a panel of experts was convened to identify, discuss and address areas of unmet need in UC. METHODS: PubMed and Cochrane Library databases were searched for relevant articles describing studies performed in patients with UC. These findings were used to generate a set of statements relating to unmet needs in UC. Consensus on these statements was then sought from a panel of 9 expert gastroenterologists using a modified Delphi review process that consisted of anonymous surveys followed by live meetings. RESULTS: In 2 literature reviews, over 5,000 unique records were identified and a total of 138 articles were fully reviewed. These were used to consider 26 areas of unmet need, which were explored in 2 face-to-face meetings, in which the statements were debated and amended, resulting in consensus on 30 final statements. The unmet needs identified were categorised into 7 areas: impact of UC on patients' daily life; importance of early diagnosis and treatment; drawbacks of existing treatments; urgent need for new treatments; and disease-, practice- or patient-focused unmet needs. CONCLUSIONS: These expert group meetings found a number of areas of unmet needs in UC, which is an important first step in tackling them in the future. Future research and development should be focused in these areas for the management of patients with UC.

Comparison of different histological indexes in the assessment of UC activity and their accuracy regarding endoscopic outcomes and faecal calprotectin levels.

OBJECTIVE: Histological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems-Geboes Score (GS), Nancy Index (NI) and RobartsHistopathologyIndex (RHI), as well as to evaluate their association with the endoscopic outcomes and the faecal calprotectin (FC) levels. DESIGN: Biopsy samples from 377 patients with UC were blindly evaluated using GS, NI and RHI. The results were compared with the patients' Mayo Endoscopic Score and FC levels. RESULT: GS, NI and RHI have a good concordance concerning the distinction between patients in histological remission or activity. RHI was particularly close to NI, with 100% of all patients classified as being in remission with NI being identified as such with RHI and 100% of all patients classified as having activity with RHI being identified as such with NI. These scores could also predict the Mayo Endoscopic Score and the FC levels, with their sensitivity and specificity levels depending on the chosen cut-offs. Moreover, higher FC levels were statistically associated with the presence of neutrophils in the epithelium, as well as with ulceration or erosion of the intestinal mucosa. CONCLUSIONS: GS, NI and RHI histopathological scoring systems are comparable in what concerns patients' stratification into histological remission/activity. Additionally, FC levels are increased when neutrophils are present in the epithelium and the intestinal mucosa has erosions or ulcers. The presence of neutrophils in the epithelium is, indeed, the main marker of histological activity.

The risk of disabling, surgery and reoperation in Crohn's disease - A decision tree-based approach to prognosis.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease known to carry a high risk of disabling and many times requiring surgical interventions. This article describes a decision-tree based approach that defines the CD patients' risk or undergoing disabling events, surgical interventions and reoperations, based on clinical and demographic variables. MATERIALS AND METHODS: This multicentric study involved 1547 CD patients retrospectively enrolled and divided into two cohorts: a derivation one (80%) and a validation one (20%). Decision trees were built upon applying the CHAIRT algorithm for the selection of variables. RESULTS: Three-level decision trees were built for the risk of disabling and reoperation, whereas the risk of surgery was described in a two-level one. A receiver operating characteristic (ROC) analysis was performed, and the area under the curves (AUC) Was higher than 70% for all outcomes. The defined risk cut-off values show usefulness for the assessed outcomes: risk levels above 75% for disabling had an odds test positivity of 4.06 [3.50-4.71], whereas risk levels below 34% and 19% excluded surgery and reoperation with an odds test negativity of 0.15 [0.09-0.25] and 0.50 [0.24-1.01], respectively. Overall, patients with B2 or B3 phenotype had a higher proportion of disabling disease and surgery, while patients with later introduction of pharmacological therapeutic (1 months after initial surgery) had a higher proportion of reoperation. CONCLUSIONS: The decision-tree based approach used in this study, with demographic and clinical variables, has shown to be a valid and useful approach to depict such risks of disabling, surgery and reoperation.

Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom Study.

BACKGROUND: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe. METHODS: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (€) using the Danish Health Costs Register. RESULTS: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was €5,408,174 (investigations: €2,042,990 [38%], surgery: €1,427,648 [26%], biologicals: €781,089 [14%], and standard treatment: €1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations €1803 (€2160) (P = 0.44), surgery €11,489 (€13,973) (P = 0.14), standard treatment €1027 (€824) (P = 0.51), and biologicals €7376 (€8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations €1189 ( €1518) (P < 0.01), surgery €18,414 ( €12,395) (P = 0.18), standard treatment €896 ( €798) (P < 0.05), and biologicals €5681 ( €72) (P = 0.51). CONCLUSIONS: In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents.

Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study.

BACKGROUND: The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. AIM: To construct and validate a web-based inception cohort database available in both English and Russian language. METHOD: The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. RESULTS: The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. CONCLUSION: A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.