Assessment of extraintestinal manifestations in inflammatory bowel diseases: A systematic review and a proposed guide for clinical trials.

BACKGROUND AND AIMS: Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations. METHODS: We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations. RESULTS: Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics. CONCLUSIONS: In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.

Dose Escalation Assessment Among Targeted Immunomodulators in the Management of Inflammatory Bowel Disease.

BACKGROUND: The need for individualized treatment regimens is becoming more important in the management of patients with inflammatory bowel disease (IBD). Gastroenterologists may dose adjust either by increasing the dose or shortening the dosing interval from the initial recommended maintenance dose to achieve an appropriate clinical response. Understanding the role of dose escalation in the treatment of IBD in clinical practice provides payers in the United States insight into the real-world cost-effectiveness of targeted immunomodulators (TIMs) in the management of IBD. OBJECTIVE: To assess the prevalence and magnitude of dose escalation for approved IBD therapies. METHODS: Using the Source Healthcare Analytics database, patients with IBD who initiated treatment with a drug of interest from July 2015 to June 2017 were identified. Patient utilization of the TIMs was tracked for 12 months following initiation. All included patients had at least 2 diagnoses for ulcerative colitis or Crohn disease before TIM initiation and at least 5 claims for a drug of interest within the 12 months following initiation. Dose escalation was defined as an increase of at least 30% in the average daily dose (ADD) relative to the patient's expected maintenance dose on 2 consecutive prescriptions. The proportion of patients with dose escalation in the first 12 months after treatment initiation was determined. The magnitude of dose escalation was determined by calculating the patient's ADD across all noninduction dose claims and comparing it with the expected daily dose. Dose escalation prevalence and magnitude were used to quantify the equivalent patient treatment rate representing the number of patients per 100 that could have been treated with standard dosing, given the prevalence of dose escalation in the treated population. RESULTS: 7,028 patients (2,406 infliximab, 1,966 adalimumab, 1,745 vedolizumab, 472 ustekinumab, 285 certolizumab pegol, and 154 golimumab) met eligibility criteria and were included in the study. Among IBD therapies, dose escalation occurred most frequently with infliximab (39%), followed by adalimumab (28%), vedolizumab (23%), ustekinumab (22%), certolizumab pegol (20%), and golimumab (14%). The magnitude of dose escalation was greatest for ustekinumab (131%), followed by infliximab (70%), vedolizumab (62%), adalimumab (59%), certolizumab pegol (50%), and golimumab (45%). The calculated patient equivalence was highest for infliximab (128) and ustekinumab (128) compared with adalimumab (116), vedolizumab (114), certolizumab pegol (110), and golimumab (106). CONCLUSIONS: Among patients with IBD, dose escalation occurred with all TIMs examined with varying degrees of prevalence and magnitude. Real-world utilization patterns of TIMs indicate that dose escalation is an important part of the clinical management of IBD and needs to be considered when evaluating the cost-effectiveness of IBD treatments. DISCLOSURES: Financial support for this study was provided by AbbVie, which participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Ehrenberg and McDonald are employees of IQVIA, which received funding from AbbVie to participate in this research. Griffith and Theigs are employed by AbbVie and may own stock or stock options in AbbVie.

Is Crohn's Disease the Price to Pay Today for Having Survived the Black Death?

BACKGROUND AND AIMS: Nucleotide Oligomerisation Domain 2 [NOD2] is a key gene of innate immunity which participates in the host defence against pathogens. Several loss-of-function NOD2 mutations are associated with Crohn's disease [CD]. Their high frequencies in populations of European ancestry suggest a model of balancing selection. Because NOD2 deficiency has been associated with a resistance to Yersinia pseudotuberculosis in mice, we hypothesised that NOD2 mutations have been selected during past plague outbreaks due to the closely related bacterium Yersinia pestis. METHODS: Contemporary frequencies of the main CD-associated NOD2 mutations [R702W, G908R, and 1007fs], measured in healthy people from European and Mediterranean countries, were collected from 60 studies via a PubMed search. Plague exposure was calculated from a dataset providing outbreaks from 1346 to 1860 in Europe and the Mediterranean Bassin. A plague index was built to capture the intensity of plague exposure in the studied geographical areas. RESULTS: NOD2 mutation frequencies were associated with the past exposure to plague. Statistical significance was obtained for the most frequent mutation [R702W, p = 0.03] and for the pooled three mutations [p = 0.023]. The association remained significant when putative demographic biases were considered. CONCLUSIONS: This result argues for a selection of CD-associated NOD2 mutations by plague outbreaks and further questioned the role of exposure to enteropathogenic Yersinia species in CD.

Incidence and Management of Infusion Reactions to Infliximab in an Alternate Care Setting.

BACKGROUND: Infliximab is a chimeric anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody that ameliorates inflammation when it binds to and neutralizes TNF-α. It is often used in patients with Crohn's disease and ulcerative colitis to reduce the severity of disease symptoms and induce disease remission. Infusions are generally administered in the hospital setting due to concerns over patient safety, and limited data exist regarding the incidence and management of infusion reactions (IRs) in an alternate care setting without direct physician oversight. AIMS: The aim of this study was to evaluate the incidence of IRs following administration of infliximab and associated management approaches in an alternate care setting. METHODS: A retrospective chart review of 796 patients with Crohn's disease or ulcerative colitis that received a combined 5581 infusions with one home infusion provider between January 2014 and November 2016 was conducted. Timing, severity, management approach, and outcomes of IRs were abstracted and analyzed. RESULTS: A total of 109 infusion reactions (2.0% of all infusions) were recorded in 62 patients (7.8% of all patients). The majority of these reactions were acute and mild or moderate in severity and resolved with rate adjustments and/or medication. Emergency room visits were required in 0.1% of all infusions, and 0.3% of all infusions were not completed due to a reaction. CONCLUSIONS: IRs to infliximab were uncommon and mostly mild or moderate in severity. Resolution of the IR and continuation of therapy was achieved in most patients through a management approach that included prompt recognition and initial treatment via rate adjustments and medications according to physician's orders.

Reduced Imaging Radiation Exposure and Costs Associated with Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

BACKGROUND: Radiation exposure from diagnostic imaging may increase cancer risk of Crohn's disease (CD) patients, who are already at increased risk of certain cancers. AIM: To compare imaging radiation exposure and associated costs in CD patients during the year pre- and post-initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: Adults were identified from a large US claims database between 1/1/2005 and 12/31/2009 with ≥ 1 abdominal imaging scan and 12 months of enrollment before and after initiating therapy with anti-TNF or corticosteroids. Imaging utilization, radiation exposure, and healthcare costs pre- and post-initiation were examined. RESULTS: Anti-TNF-treated patients had significantly fewer imaging examinations the year prior to initiation than corticosteroid-treated patients. Cumulative radiation doses before initiation were significantly higher for corticosteroid patients compared to anti-TNF patients (22.3 vs. 17.7 millisieverts, P = 0.0083). After therapy initiation, anti-TNF-treated patients had significantly fewer imaging examinations (2.9 vs. 5.2, P < 0.0001) and less radiation exposure (7.4 vs. 15.4 millisieverts, P <0.0001) than corticosteroid-treated patients in the follow-up period. Reductions in imaging costs adjusted for 1000 patient-years after initiation of therapy were - $275,090 and - $121,960 (P = 0.0359) for anti-TNF versus corticosteroid patients, respectively. CONCLUSIONS: This analysis demonstrated that patients treated with anti-TNF agents have fewer imaging examinations, less radiation exposure, and lower healthcare costs associated with imaging than patients treated with corticosteroids. These benefits do not account for additional long-term benefits that may be gained from reduced radiation exposure.

Biosimilars in paediatric inflammatory bowel disease.

The introduction of biological treatments has changed disease outcomes for patients with inflammatory bowel disease. Biologicals have high efficacy, and can induce and maintain remission after failed responses to conventional immunosuppressive and/or steroid therapy. The increasing occurrence of severe disease at diagnosis has resulted in infliximab being more often introduced as the first-line treatment in a "top-down" approach. Besides their favourable efficacy and safety profile, biologicals have one significant disadvantage, which is their high cost. This results in many patients stopping therapy prematurely, with the maintenance phase being too short. This often leads to disease exacerbation shortly after treatment cessation. Every newly started course of biological therapy can induce production of anti-drug antibodies, which can result in treatment failure and possible allergic/anaphylactic reactions. The introduction of biological biosimilars was intended to greatly reduce therapy costs thus increasing the availability of these agents to more patients. It was also anticipated that biosimilars would prevent premature termination of therapy. Analyses of paediatric data suggest that biosimilar infliximabs are equally effective as the reference infliximab. Safety patterns also seem to be similar. Paediatric experience places cost-therapy reductions at around 10%-30%.

Immunohistochemical Assessment of CD30+ Lymphocytes in the Intestinal Mucosa Facilitates Diagnosis of Pediatric Ulcerative Colitis.

BACKGROUND: Diagnosis of pediatric inflammatory bowel diseases (IBD) remains challenging. We aimed at the value of immunohistochemical assessment of CD30+ lymphocytes in the intestinal mucosa in differential diagnosis between pediatric Crohn's disease (CD) and ulcerative colitis (UC) and its utility as a predictor of future differentiation in patients with IBD unclassified (IBDU). METHODS: Seventy-four treatment naive pediatric patients with IBD (33 CD, 30 UC and 11 IBDU) were enrolled into the study. Biopsy samples from six different regions (terminal ileum, cecum, ascending colon, transverse colon, descending colon and rectum) were immunohistochemically stained with anti-CD30 antibody, and the number of positive cells per one high power field was quantified. RESULTS: Significant differences between CD and UC were found when compared total counts of CD30+ cells in median numbers, mean values and maximal numbers and also for separate counts in terminal ileum, transverse colon, descending colon and rectum. The most profound difference between CD and UC was shown for total median values of CD30+ cells and for the values in rectal localization. The difference was independent on the intensity of inflammation. A cutoff value of 2.5 CD30+ cells with sensitivity 83% and specificity 90% was found for the rectum. There was no difference between patients with CD and IBDU, but a marked difference between UC and IBDU patients was revealed. CONCLUSION: Histopathological assessment of biopsy with rectal CD30+ count is reliable and simple method that could help in differential diagnosis among IBD subtypes in children with IBD.

Detection of anti-infliximab antibodies in Slovak IBD patients and its costs saving effect.

OBJECTIVE: Management chronic inflammatory bowel disease (IBD) patients is associated with diagnosis, targeted treatment and and individual approach. There is a group of patients which loss the response to the biologic treatment caused by insufficient levels of biologics or positive antibodies against these drugs. This study was aimed to determine the prevalence of patients with positive antibodies against the biological treatment and the costs saving probabilities of the antibodies detection during the treatment. STUDY DESIGN: This retrospective study was based on examination of 183 IBD patients' sera (72 with Crohn's disease (CD) and 111 ulcerative colitis (UC)) treated with infiliximab. METHODS: Circulating serum infliximab concentrations and anti-infliximab antibodies (ATI) were quantified by ELISA methods. Costs associated with the treatment were analysed from the data of General Health Insurance Company, Slovakia. RESULTS: The average infliximab concentrations in groups of CD were 2.9 µg/mL, 38.9% of samples had a concentration ≤1 µg/mL. Group with UC had average infliximab levels of 3.19 µg/mL, 32.4% bellow ≤1 µg/mL. Positive ATI levels were detected in 52 patients, in 28 patients with CD (38.8%) and 24 patients with UC (21.6%). The average values of the antibodies were 387.75 U/ml in CD and 391.94 U/ml in UC group. More than 28% IBD patients were positive for ATI. After application of the results to the database of all IBD patients, finishing of the treatment with ATI could lead (after considering the ATI quantification costs) to possible annual savings of more than €2 million in Slovakian health-care system. CONCLUSIONS: Monitoring of infliximab and antibodies against infliximab and anti-TNF-α biologics may help optimize treatment strategies and costs for biological treatment.

Does Helicobacter pylori eradication therapy trigger or protect against Crohn's disease?

Helicobacter pylori (H. pylori) infection is involved in multiple gastrointestinal and extra-gastrointestinal disorders. This review focuses on possible link between H. pylori eradication and Crohn's disease (CD) which is a chronic inflammatory bowel disease (IBD). Fecal calprotectin and; to lesser extent; fecal lactoferrin are sensitive and specific markers for monitoring CD activity. Data about link between H. pylori eradication and CD are limited and inconclusive. The infection likely shifts equilibrium between T helper 1 (Th1) and Th2 immune responses to the Th2 pattern. In subjects genetically predisposed to CD (a Th1-related disease), H. pylori eradication increases Th1 proinflammatory cytokines causing development of CD. In contrast, clarithromycin and/or proton pump inhibitors that are used to eradicate H. pylori can suppress Th1 factors, and theoretically can protect against CD, but there are no data to support this supposition. This Th1/Th2 approach seems very simplistic. Another theory is that alterations in gut microbiota form "continuous antigenic stimulation" predisposing to IBD. H. pylori infection can inhibit such stimulation through activation of regulatory T cells, and thus eradication may predispose to CD. Probiotics weren't found useful in treatment of CD. The reported data about link between H. pylori eradication and CD are currently limited. Case reports, suggesting a positive association between both conditions, provide a very little evidence. On eradicating H. pylori in CD patients and/or patients with high risk for CD, patient counseling and follow-up in addition to measuring fecal calprotectin may help monitor CD activity. (Acta gastro-enterol. belg., 2016, 79, 349-354).

(1)H-NMR based metabolomics study for the detection of the human urine metabolic profile effects of Origanum dictamnus tea ingestion.

(1)H NMR spectroscopy was employed to investigate the repercussion of Origanum dictamnus tea ingestion in several volunteers' urine metabolic profiles, among them two with chronic inflammatory bowel diseases (IBD), mild IBD and Crohn's disease. Herein, we demonstrate that the concentrations of a lot of urinary metabolites such as hippurate, trimethylamine oxide (TMAO), citrate, and creatinine are altered, which prompts the intestinal microflora function/content perturbation as well as kidney function regulation by dictamnus tea. Interestingly, our preliminary results showed that a high dose of dictamnus tea intake appeared to be toxic for a person with Crohn's disease, since it caused high endogenous ethanol excretion in urine. All subjects' metabolic effects caused by the dictamnus tea appeared to be reversible, when all volunteers stopped its consumption. Finally, we highlight that individuals' metabolic phenotype is reflected in their urine biofluid before and after the dictamnus tea effect while all individuals have some common and different metabolic responses to this tea, implying that each phenotype has a quite different response to this tea consumption.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Quantitative assessment of CD30+ lymphocytes and eosinophils for the histopathological differential diagnosis of inflammatory bowel disease.

BACKGROUND AND AIMS: The histopathological discrimination of Crohn's disease [CD] and ulcerative colitis [UC] can be challenging. The aim of this study was to evaluate if quantification of CD30(+) lymphocytes and eosinophils in histopathological material improves the accuracy of diagnosis of inflammatory bowel disease. METHODS: A total of 156 patients were diagnosed with IBD by a gastroenterologist and corroborated by 5 years of follow-up. Patients were treatment naïve at the time of biopsy. Samples were taken from diseased areas of the colon and examined by a gastrointestinal pathologist. RESULTS: The median number of eosinophils in biopsies from affected segments was 42/high power field [hpf] [25.5-63.5] in CD and 98/hpf [67-123] in UC [p < 0.001]. Biopsies containing ≥ 70 eosinophils/hpf field had a sensitivity of 78.3% and a specificity of 71% for the diagnosis of UC ({area under the receiver operating characteristic (ROC) curve 0.767 (95% confidence interval [CI] 0.696-0.838)}. There was a median of three CD30(+) cells/hpf [range 2-6] in diseased CD biopsies and 33 cells/hpf [24-52] in diseased UC biopsies [p < 0.001]. The cut-off determined by the ROC curve was 15 (sensitivity 97.4%, specificity 97.4%, positive likelihood ratio (PLR) 17.1, Negative likelihood ratio (NLR) 0.03, area under the curve [AUC]: 0.978; 95% CI 0.95310.999). CONCLUSIONS: Routine histopathological assessment with quantification of CD30+ cells is highly accurate at discriminating CD and UC. All the measured parameters are easy to perform, low-cost, and available in most pathological laboratories.

Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 µg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 µg/mL (43.7%). Of 76 patients with TCs <3 µg/mL, 69 patients (91%) achieved TCs of 3-7 µg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 µg/mL, 67 patients (93%) achieved TCs of 3-7 µg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 µg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.

Biological therapy in inflammatory bowel diseases: access in Central and Eastern Europe.

Biological drugs opened up new horizons in the management of inflammatory bowel diseases (IBD). This study focuses on access to biological therapy in IBD patients across 9 selected Central and Eastern European (CEE) countries, namely Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia. Literature data on the epidemiology and disease burden of IBD in CEE countries was systematically reviewed. Moreover, we provide an estimation on prevalence of IBD as well as biological treatment rates. In all countries with the exception of Romania, lower biological treatment rates were observed in ulcerative colitis (UC) compared to Crohn's disease despite the higher prevalence of UC. Great heterogeneity (up to 96-fold) was found in access to biologicals across the CEE countries. Poland, Bulgaria, Romania and the Baltic States are lagging behind Hungary, Slovakia and the Czech Republic in their access to biologicals. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but association with other possible determinants (differences in prevalence and incidence, price of biologicals, total expenditure on health, geographical access, and cost-effectiveness results) was not proven. We assume, nevertheless, that health deterioration linked to IBD might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilization of biological drugs for IBD. In conclusion, access to biologicals varies widely among CEE countries and this difference cannot be explained by epidemiological factors, drug prices or total health expenditure. Changes in reimbursement policy could contribute to better access to biologicals in some countries.

Patients' assessment of adalimumab self-injection for Crohn's disease: a multicenter questionnaire survey (The PEARL Survey).

BACKGROUND/AIMS: Adalimumab (ADA) is a self-injectable anti-tumor necrosis factor-α antibody used for treating Crohn's disease (CD). Although self-injecting ADA may be convenient for patients, few reports have assessed patients receiving ADA self-injection therapy. METHODOLOGY: We conducted a questionnaire survey involving outpatients on ADA self-injection therapy at four university hospitals. We analyzed the degree of satisfaction with and adherence to the self-injection therapy and performed sub-analyses. RESULTS: Responses were obtained from 124 patients. Before treatment initiation, 38% patients replied that they were unwilling to accept the self-injection therapy. However, after treatment initiation, 75% patients were satisfied with the treatment. 66 patients previously treated with infliximab (IFX), the degree of treatment satisfaction was significantly higher in patients who felt burdened to the time required for IFX infusion than in those who had not felt burdened (P < 0.05). Patient adherence to ADA was high (85%). Multivariate analysis regarding adherence revealed that duration of disease (OR, 0.99), degree of treatment efficacy satisfaction (OR, 13.42), and schedule registration (OR, 7.95) were significant. Safety assessment results were within the range of those already reported. CONCLUSIONS: ADA self-injection was thought to have good adherence and a safe administration method according to patients' assessments.

Biological therapies in Crohn's disease: are they cost-effective? A critical appraisal of model-based analyses.

In refractory Crohn's disease, anti-TNF and anti-α 4 integrin agents are used for ameliorating disease activity but impose high costs to health-care systems. The authors systematically reviewed cost-effectiveness analyses based on decision models: most of the studies were judged to have a good quality, but a large portion assessed health and costs in a short time horizon, usually disregarding fistulizing disease and not considering safety. Infliximab induction followed by on-demand retreatment consistently proved to have a good cost per quality-adjusted life year, while maintenance treatment never satisfied commonly accepted cost-utility thresholds. Challenges in cost-effectiveness analysis include the lack of a standard model structure, a large variability in the costs of surgery and poor data on indirect costs. As clinical practice is moving to mucosal healing as a robust response marker, personalized schedules of anti-TNF therapies might prove cost-effective even in the perspective of the health-care system in the near future.

Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs.

Ulcerative colitis and Crohn's disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients' own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients' disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.

Optimizing screening for tuberculosis and hepatitis B prior to starting tumor necrosis factor-α inhibitors in Crohn's disease.

BACKGROUND AND AIMS: Treatment with tumor necrosis factor-α (TNF-α) inhibitors in patients with Crohn's disease (CD) is associated with potentially serious infections, including tuberculosis (TB) and hepatitis B virus (HBV). We assessed the cost-effectiveness of extensive TB screening and HBV screening prior to initiating TNF-α inhibitors in CD. METHODS: We constructed two Markov models: (1) comparing tuberculin skin test (TST) combined with chest X-ray (conventional TB screening) versus TST and chest X-ray followed by the interferon-gamma release assay (extensive TB screening) in diagnosing TB; and (2) HBV screening versus no HBV screening. Our base-case included an adult CD patient starting with infliximab treatment. Input parameters were extracted from the literature. Direct medical costs were assessed and discounted following a third-party payer perspective. The main outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity and Monte Carlo analyses were performed over wide ranges of probability and cost estimates. RESULTS: At base-case, the ICERs of extensive screening and HBV screening were €64,340 and €75,760 respectively to gain one quality-adjusted life year. Sensitivity analyses concluded that extensive TB screening was a cost-effective strategy if the latent TB prevalence is more than 12 % or if the false positivity rate of TST is more than 20 %. HBV screening became cost-effective if HBV reactivation or HBV-related mortality is higher than 37 and 62 %, respectively. CONCLUSIONS: Extensive TB screening and HBV screening are not cost-effective compared with conventional TB screening and no HBV screening, respectively. However, when targeted at high-risk patient groups, these screening strategies are likely to become cost-effective.

Impact of JC virus antibody testing in patients with Crohn's disease with loss of response to infliximab: a Markov model.

BACKGROUND: The optimal treatment strategy for patients with Crohn's disease who have loss of response to the anti-tumor necrosis factor α medication infliximab is uncertain. Natalizumab has an alternative mechanism of action, but its use has been limited by the risk of progressive multifocal leukoencephalopathy. In this study, we performed a decision analysis assessing the impact of JC virus (JCV) antibody testing and natalizumab utilization for loss of response to infliximab. METHODS: We constructed a Markov model to assess the difference between unscreened natalizumab use (option 1), JCV antibody testing with natalizumab when appropriate (option 2), and second anti-tumor necrosis factor α use (option 3). The base case was a 35-year-old man with severe Crohn's disease with loss of response to infliximab. The time horizon was 3 years. Results are reported in quality-adjusted life years (QALYs). Deterministic and probabilistic analyses were conducted. Markov analysis using a cohort of 5000 individuals was performed. The impact of JCV antibody status on outcomes in this model was assessed. RESULTS: Option 2 was the preferred strategy (2.0880 QALYs), followed by option 1 (2.0875 QALYs) and option 3 (2.0808 QALYs). Patients in option 2 required fewer surgeries compared with option 3. Previous JCV infection was associated with reduced QALYs with all options that allowed for natalizumab use. CONCLUSIONS: JCV antibody testing and subsequent treatment selection yield improved outcomes over natalizumab without testing or using only a second anti-tumor necrosis factor α in all patients.

Use of the tumor necrosis factor-blockers for Crohn's disease.

The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn's disease study thirty years ago. The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses. In general, it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1) for persons with moderately-severe Crohn's disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids. Once TNFBs have been introduced and the patient is responsive, therapy given by the IV and SC rate must be continued. It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy, and when or if TNFB may be weaned and discontinued. The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient's illness needs to be confirmed. The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB, and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic. Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high, the ultimate application of use of TNFBs will likely be established by cost/benefit studies.