Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000.

BACKGROUND: For smokers not intending to quit, switching to a reduced-risk nicotine product should be healthier than continuing smoking. We estimate the health impact, over the period 2000-2050, had the nicotine pouch ZYN hypothetically been introduced into the US in 2000. ZYN's toxicant profile and method of use is like that for Swedish snus, a product with known health effects much less than smoking. METHODS: Our modelling approach is similar to others developed for estimating potential effects of new tobacco products. It starts with a simulated cohort of 100,000 individuals in the year 2000 subdivided by age, sex, and smoking status (including years since quitting). They are followed annually accounting for births, net immigrations, deaths and product use changes, with follow-up carried out in the Base Case (ZYN not introduced) and Modified Case (ZYN introduced). Using informed assumptions about initiation, quitting and switching rates, distributions of the population over time are then constructed for each Case, and used to estimate product mortality based on assumptions about the relative risk according to product use. RESULTS: Whereas in both Base and Modified Cases, the prevalence of any current product use is predicted to decline from about 22% to 10% during follow-up, in the Modified Case about 25% of current users use ZYN by 2050, about a quarter being dual users and the rest ZYN-only users. Over the 50 years, deaths at ages 35-84 from product use among the 100,000 are estimated as 249 less in the Modified than the Base Case, equivalent to about 700,000 less in the whole US. Sensitivity analyses varying individual parameter values confirm the benefits of switching to ZYN, which increase as either the switching rate to ZYN increases or the initiation rate of ZYN relative to smoking increases. Even assuming the reduction in excess mortality risk using ZYN use is 20% of that from smoking rather than the 3.5% assumed in the main analyses, the reduction in product-related deaths would still be 213, or about 600,000 in the US. CONCLUSIONS: Although such model-based estimates involve uncertainties, the results suggest that introducing ZYN could substantially reduce product-related deaths.

Comparison of fecal calprotectin and serum C-reactive protein in early prediction of outcome to infliximab induction therapy.

Background: Fecal calprotectin (FC) and serum C-reactive protein (CRP) are biomarkers of disease activity in Crohn's disease (CD) and ulcerative colitis (UC). We assessed FC, CRP, Harvey-Bradshaw index (HBi), partial Mayo Clinic Scoring (pMCS) and a cytokine panel during infliximab induction to predict therapy outcome. Methods: FC, CRP and clinical indices were evaluated in 123 (76 CD, 47 UC) patients before infliximab induction and after 12 weeks. Responders were monitored 48 weeks for an 'incident' (dosage increase, shortened dosage interval, surgery). Cutoff values for FC and CRP were obtained using receiver-operating characteristics (ROC). Disease progression was analyzed with Kaplan-Meier survivals, log-rank test and logistic regression for combined biomarkers. Cytokines were analyzed with Luminex multiplexing system. Results: Following infliximab, FC and CRP declined (p < .0001) along with HBi for CD and pMCS for UC. Simultaneously, IL-6 and TNF-α decreased, while IL-10 increased. Optimal FC ROC cutoff was 221 µg/g (sensitivity 66%, specificity 67%, AUC 0.71) and CRP ROC cutoff 2.1 mg/L (sensitivity 54%, specificity 60%, AUC 0.58). In CD, FC > 221 µg/g (p < .0001), but not CRP > 2.1 mg/L predicted an 'incident'. However, combined FC and CRP also predicted an 'incident' (p < .042). In UC, both FC > 221 µg/g (p < .0005) and CRP > 2.1 mg/L (p = .0334) predicted 'incident', as did combined biomarkers (p < .005). Conclusions: Clinical disease activity is reduced by treatment with infliximab. In CD, persistently high FC, but not CRP, predict a treatment 'incident', whereas in UC both high FC and high CRP predict 'incident'. Combined FC and CRP values also predict an 'incident'.

The comparison of trial data-based and registry data-based cost-effectiveness of infliximab treatment for rheumatoid arthritis in Sweden using a modeling approach.

OBJECTIVE: To evaluate the precision of the predictive cost-effectiveness assessment based on a phase 3 clinical trial with infliximab for the treatment of rheumatoid arthritis in Swedish clinical practice. METHODS: Three patient cohorts were identified: the patients included in the infliximab trial (ATTRACT), patients initially treated with infliximab from a Swedish registry (STURE), a subset of these registry patients meeting inclusion criteria for the ATTRACT trial was the third patient cohort; two sets of assumptions in relation to the efficacy data were evaluated: "ATTRACT" (efficacy data over the duration of the trial) and "STURE" (effectiveness data over 10 years). In addition, the impact of including the placebo effect for the comparator was evaluated as a basis for the calculation of cost-effectiveness by using a modeling approach. A health economic model was utilized to estimate the cost per quality-adjusted life-year (QALY) gained. RESULTS: The results for the three patient cohorts ranged from cost saving to a cost per QALY gained of €2,400 and €24,900 to €26,000 when the ATTRACT and STURE assumptions were used, respectively. Sensitivity analyses indicated that the inclusion of placebo effect had the largest effect on the results, increasing the cost per QALY gained to approximately €50,000 for all patient cohorts. CONCLUSIONS: The treatment effect of infliximab measured in clinical trials and clinical practice results in comparable cost-effectiveness ratios, as calculated by using a modeling approach, whereas the assumptions made in relation to the effectiveness data and the chosen comparator have a large impact on the results. This reinforces the value of early modeling studies based on randomized clinical trial data, but assumptions made need to be carefully assessed.

Blood chemistry markers for evaluation of inflammatory activity in Crohn's disease during infliximab therapy.

OBJECTIVE: There is a discrepancy between clinical activity and biomarkers in inflammatory bowel disease. The Harvey-Bradshaw index (HBi) is steadfast to evaluate disease activity. A set of biological markers (high sensitive C-reactive protein [hs-CRP], calprotectin, total nitrite, soluble urokinase Plasminogen Activator Receptor [suPAR], ghrelin and endothelin) are investigated to study inflammatory activity and correlation with HBi during infliximab therapy. MATERIAL AND METHODS: Patients with Crohn's disease (n = 22) were assessed and blood samples drawn before and 1 week after infliximab infusion (5 mg/kg) and repeated after 6 months, and compared to healthy volunteers. Hs-CRP, calprotectin, suPAR, ghrelin and endothelin were analyzed with immunoassays, and total nitrite with Griess-reaction. Results were analyzed with Wilcoxon matched-pairs test, Mann-Whitney test and Spearman correlations. RESULTS: After the first infusion visit, HBi and calprotectin values decreased while nitrite increased (p < 0.05). At the 6-month visit, pre-infusion index and biomarkers had returned to baseline levels. Post-infusion, again the values of HBi, hs-CRP and calprotectin decreased (p < 0.05). The suPAR levels did not change between pre- and post-infusion periods at either visit. Calprotectin, nitrite and suPAR differed from healthy controls throughout the study (p < 0.05). Endothelin decreased with each treatment but was, like ghrelin, not different from controls. We found HBi to correlate with hs-CRP (Spearman r = 0.32, p < 0.05), but calprotectin did not, neither did nitrate nor suPAR. CONCLUSIONS: Although infliximab ameliorates Crohn's disease symptoms, inflammatory markers are not persistently normalized, indicating a chronic inflammatory condition that may require continued infliximab therapy.

Cost-effectiveness of real-world infliximab use in patients with rheumatoid arthritis in Sweden.

OBJECTIVES: The objective of this study was to estimate the cost-effectiveness of infliximab use in patients with rheumatoid arthritis (RA) in Swedish clinical practice, based on patient-level data from the Stockholm TNF-alpha follow-up registry (STURE). METHODS: Real-world patient-level data on infliximab use from the STURE registry were implemented in a Markov cohort model, in which health states of functional status were classified according to the Health Assessment Questionnaire Disability Index (HAQ-five categories) and twenty-eight joint count Disease Activity Score (DAS28). The transition probabilities between HAQ and DAS28 states during treatment, as well as discontinuation rates were modeled based on data from the registry for patients using infliximab as their first-line biological treatment. The transition probabilities in the comparator arm, that is, disease progression without biologic treatment, as well as mortality rates, costs, and utilities were based on published literature. The analysis had a societal cost perspective. RESULTS: Infliximab was associated with an incremental gain in quality-adjusted life-years of 1.02 and an incremental cost of 23,264 euros per patient compared with progression without biologic treatment, producing an incremental cost-effectiveness ratio (ICER) of 22,830 euros (SEK211,136 or US$31,230). Sensitivity analyses of input parameters and model assumptions produced ICERs in the range from 18,000 euros to 47,000 euros. CONCLUSIONS: Results from base-case and sensitivity analyses fell well below established benchmarks for cost-effectiveness in Sweden. The results, therefore, indicated that infliximab treatment for RA has provided good societal value for money in Swedish clinical practice, compared with a scenario of no biological treatment.

Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein in Response to Infliximab in Crohn's Disease.

Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity. AIMS: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNFα antibody (infliximab) induced lowering of TNFα and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNFα were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNFα was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNFα. Parallel infliximab effects on TNFα, HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.

Rectal nitric oxide as biomarker in the treatment of inflammatory bowel disease: responders versus nonresponders.

AIM: To explore rectal nitric oxide (NO) as biomarker of treatment response in ulcerative colitis (UC) and Crohn's disease (CD), and examine relationships between rectal NO, mucosal expression of NO synthases (NOS), and pro-inflammatory cytokines. METHODS: Twenty-two patients with UC and 24 with CD were monitored during steroid treatment. Rectal NO levels were measured and clinical activities were assessed on days 1, 3, 7 and 28. Mucosal presence of NOS and pro-inflammatory cytokines were analyzed by immunohistochemistry and RT-PCR. RESULTS: Active UC and CD displayed markedly increased rectal NO levels (10950 +/- 7610 and 5040 +/- 1280 parts per billion (ppb), respectively) as compared with the controls (154 +/- 71 ppb, P < 0.001). Rectal NO correlated weakly with disease activity in both UC and CD (r = 0.34 for UC and r = 0.48 for CD, P < 0.01). In 12 patients, a steroid-refractory course led to colectomy. These patients had only slightly increased NO levels (UC: 620 +/- 270 ppb; CD: 1260 +/- 550 ppb) compared to those with a therapeutic response (UC: 18860 +/- 530 ppb, P < 0.001; CD: 10060 +/- 3200 ppb, P < 0.05). CONCLUSION: Rectal NO level is a useful biomarker of treatment response in IBD as low NO levels predicts a poor clinical response to steroid treatment.

Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY.

BACKGROUND AND AIM: Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls. METHODS: Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY. RESULTS: Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients. CONCLUSION: The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

A maximum likelihood estimator of a Markov model for disease activity in Crohn's disease and ulcerative colitis for annually aggregated partial observations.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases that have a remitting, relapsing nature. During relapse, they are treated with drugs and surgery. The present study was based on individual data from patients diagnosed with CD or UC at Herlev University Hospital, Copenhagen, Denmark, during 1991 to 1993. The data were aggregated over calendar years; for each year, the number of relapses and the number of surgical operations were recorded. Our aim was to estimate Markov models for disease activity in CD and UC, in terms of relapse and remission, with a cycle length of 1 month. The purpose of these models was to enable evaluation of interventions that would shorten relapses or postpone future relapses. An exact maximum likelihood estimator was developed that disaggregates the yearly observations into monthly transition probabilities between remission and relapse. These probabilities were allowed to be dependent on the time since start of relapse and on the time since start of remission, respectively. The estimator, initially slow, was successfully optimized to shorten the execution time. The estimated disease activity model for CD fits well to observed data and has good face validity. The disease activity model is less suitable for UC due to its transient nature through the presence of curative surgery.

Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease: the first 100 patients treated in Scandinavia.

OBJECTIVE: Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. MATERIAL AND METHODS: Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). RESULTS: The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). CONCLUSIONS: Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.

Rectal mucosal nitric oxide in differentiation of inflammatory bowel disease and irritable bowel syndrome.

BACKGROUND & AIMS: Differentiating patients with functional bowel disorders from those with inflammatory bowel disease (IBD) can be difficult. Rectal luminal levels of nitric oxide (NO) are greatly increased in IBD. To further evaluate this disease marker, we compared NO in patients with irritable bowel syndrome (IBS) with those found in patients with active IBD and in healthy control subjects. METHODS: Rectal NO was measured with chemiluminescence technique by using a tonometric balloon method in 28 healthy volunteers, 39 patients with IBS, 86 with IBD (Crohn's disease and ulcerative colitis), and 12 patients with collagenous colitis. In addition, NO was measured before and after a 4-week treatment period in patients with active ulcerative colitis and repeatedly during 2 weeks in healthy volunteers. RESULTS: NO was low in healthy control subjects (median, 45; 25th-75th percentile, 34-64 parts per billion [ppb]), and variations over time were small. In IBS patients NO was slightly increased (150, 53-200 ppb; P < .001), whereas patients with active IBD or collagenous colitis had greatly increased NO levels (3475, 575-8850 ppb, and 9950, 4475-19,750 ppb, respectively; P < .001). With a cutoff level of 250 ppb, NO had a sensitivity of 95% and a specificity of 91% in discriminating between active bowel inflammation and IBS. Rectal NO correlated with disease activity in IBD and collagenous colitis and decreased markedly in IBD patients responding to anti-inflammatory treatment. CONCLUSIONS: Rectal NO is a minimally invasive and rapid tool for discriminating between active bowel inflammation and IBS and a possibly useful add-on for monitoring patients with IBD.

Increased rectal nitric oxide in children with active inflammatory bowel disease.

BACKGROUND: Luminal nitric oxide increases in ulcerative colitis and Crohn disease. The authors have previously used a minimally invasive method to demonstrate increased luminal nitric oxide in ulcerative colitis and Crohn disease of the colon. The aim of the current study was to determine whether this method could be applied to identify inflammatory activity in ulcerative colitis and Crohn disease in children. METHODS: Thirty-six children (18 of whom had active disease) with inflammatory bowel disease localized to the colon were studied. The control group comprised 12 healthy children. To measure nitric oxide, a silicon catheter with an inflatable balloon was inserted into the rectum and inflated with 10 mL of nitric oxide-free air. After a 10-minute incubation time, the air was withdrawn and nitric oxide concentrations were immediately analyzed using a chemiluminescence technique. RESULTS: Children with active ulcerative colitis and Crohn disease of the colon had greatly increased luminal nitric oxide concentrations in the rectum (8,840 +/- 5,120 and 15,170 +/- 4,757 parts per billion [ppb], respectively) compared with controls (77 +/- 17 ppb) (P < 0.001). Children with nonactive ulcerative colitis or Crohn disease displayed low concentrations of rectal nitric oxide (356 +/- 110 and 188 +/- 55 ppb, respectively), which was not different from that of healthy controls. CONCLUSION: Rectal nitric oxide measurement is a feasible and useful method for monitoring disease activity in inflammatory bowel disease, especially in children.