Simulated cost-effectiveness of a novel precision-guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy.

BACKGROUND: Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS). METHODS: We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4-week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA). RESULTS: PGD was the cost-effective IFX dosing strategy with an ICER of 122,932 $ per quality-adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One-way sensitivity analysis demonstrated that the cost-effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results. CONCLUSIONS: PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost-effective under conservative assumptions.

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

Corrigendum: Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

[This corrects the article DOI: 10.3389/fimmu.2024.1342477.].

Older Adults With Inflammatory Bowel Disease Are at Higher Risk of Developing Antibodies to Infliximab.

Although older age is thought to confer immunosenescence, we found that older adults with inflammatory bowel disease are independently at higher risk to develop antibodies to infliximab. Additionally, older adults are less likely to receive escalated doses of infliximab.

Nutritional Biomarkers for the Prediction of Response to Anti-TNF-α Therapy in Crohn's Disease: New Tools for New Approaches.

Crohn's disease (CD) is a chronic disorder of the digestive tract characterized by an uncontrolled immune-mediated inflammatory response in genetically predisposed individuals exposed to environmental risk factors. Although diet has been identified as one of the major environmental risk factors, the role of nutrients in the clinical management of CD patients has not yet been fully investigated. In this prospective observational study, fifty-four patients diagnosed with active Crohn's disease and undergoing anti-TNF-α biological therapy were enrolled and subjected to nutrient intake analysis through a daily food diary. Their nutrient intake and blood values were analyzed before and after 6 months of biological therapy. After 6 months of anti-TNF-α, four patients dropped out of the study, leaving 29 patients in clinical remission and 21 still with active disease that remained the same. The aim of this study was to identify nutrients whose intake or blood values may be associated with patients' responses to biological therapy. In the diet, patients remaining with active CD showed very similar nutrient dietary intake compared to patients achieving remission except for a trend for lower starting zinc intake, below the reference value. In the blood, instead, patients who did not respond to biological therapy showed significantly lower plasma values of iron and taurine before starting biological anti-TNF-α treatment.

Adalimumab Clearance, Rather Than Trough Level, May Have Greatest Relevance to Crohn's Disease Therapeutic Outcomes Assessed Clinically and Endoscopically.

OBJECTIVE: We postulated that adalimumab [ADA] drug clearance [CL] may be a more critical determinant of therapeutic outcome than ADA concentration. This was tested in Crohn's disease [CD] patients undergoing ADA maintenance treatment. METHODS: CD patients from four cohorts received ADA induction and started maintenance therapy. Therapeutic outcomes consisted of endoscopic remission [ER], sustained C-reactive protein [CRP] based clinical remission [defined as CRP levels below 3 mg/L in the absence of symptoms], and faecal calprotectin [FC] level below 100 µg/g. Serum albumin, ADA concentration, and anti-drug antibody status were determined using immunochemistry and homogeneous mobility shift assay, respectively. CL was determined using a nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Mann-Whitney test and logistic regression with calculation of odds ratio. Repeated event analysis was conducted using a nonlinear mixed effect model. RESULTS: In 237 enrolled patients [median age 40 years, 45% females], median CL was lower in patients achieving ER as compared with those with persistent active endoscopic disease [median 0.247 L/day vs 0.326 L/day, respectively] [p <0.01]. There was no significant difference in ADA concentration between patients in endoscopic remission compared with those with recurrence [median 9.3 µg/mL vs 11.7 µg/mL, respectively]. Sustained CRP-based clinical remission and FC levels below 100 µg/g were generally associated with lower CL and higher ADA concentration. Repeated event analysis confirmed those findings with better performances of CL than concentration in associating with ER and other outcomes. CONCLUSION: Lower ADA clearance is associated with an improved clinical outcome for patients with Crohn's disease and may be a superior pharmacokinetic measure than concentration.

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab.

Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (p < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (p < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = -19.2; p < 0.001), and the combination of both further minimized OFV (p < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.

Real-world impact of infliximab precision-guided dosing on management of patients with IBD.

OBJECTIVES: Evaluate the clinical utility of a precision-guided dosing test for infliximab (IFX) and its impact on treatment decision-making for inflammatory bowel disease (IBD). STUDY DESIGN: Prospective, multisite, clinical experience program. METHODS: Health care providers were given access to PredictrPK IFX, a precision-guided dosing test, for their patients with IBD on maintenance IFX therapy. Blood samples were drawn 20 to 56 days post infusion. A Bayesian data assimilation tool used clinical and serologic data to generate individual pharmacokinetic profiles and forecast trough IFX. Results were reported to providers to aid in-therapy management decisions and the decision-making process was assessed through questionnaires. Relationships between forecasted IFX concentration, disease activity, and therapy management decisions were analyzed by logistic regression. RESULTS: PredictrPK IFX was used for 275 patients with IBD by 37 providers. In 58% of cases, providers modified treatment plans based on the results, including dose modifications (41%; of these, one-third decreased dose) and discontinuation (8%) of IFX. Of the 42% where treatment was not modified, 97.5% had IFX levels of 5 µg/mL or greater. Patients with IFX concentrations less than 5 µg/mL were 3 and 7.3 times more likely to have active disease or discontinue IFX, respectively. There was unanimous agreement among providers who completed a postprogram survey that PredictrPK IFX was beneficial in guiding treatment decisions and added more value to their practice than routine therapeutic drug monitoring. CONCLUSIONS: PredictrPK IFX enables earlier and more precise dose optimization of IFX in patients with IBD, exerting a substantial impact on treatment decisions that may result in improved health outcomes and overall cost savings.

Correlations Between Gastrointestinal Symptoms and Endoscopic-Histologic Disease Activity in Adults with Ulcerative Colitis.

INTRODUCTION: Discordance between gastrointestinal (GI) symptoms and endoscopic inflammation in patients with ulcerative colitis (UC) is known. However, the correlations between symptoms and endoscopic and histologic (endo-histologic) mucosal healing and remains unknown. METHODS: We performed a secondary analysis of prospectively collected clinical, endoscopic, and histologic data on 254 colonoscopies from 179 unique adults at a tertiary referral center from 2014 to 2021. Spearman's rank was used to assess the correlation between patient reported outcomes and objective assessments of disease activity, as measured by validated instruments: Two-item patient-reported outcome measure (PRO-2) for stool frequency and rectal bleeding, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for endoscopic inflammation, and the Geboes score for histologic inflammation. The predictive value of objective assessments of inflammation and clinical symptoms was described using sensitivity, specificity, and positive/negative predictive value. RESULTS: One-quarter (28%, 72/254) of cases were in endo-histologic remission; of these, 25% (18/72) report GI symptoms (22% diarrhea; 6% rectal bleeding). Endo-histologically active disease had higher sensitivity (95% rectal bleeding; 87% diarrhea) and negative predictive value (94% rectal bleeding, 78% diarrhea) for clinically active disease compared to active disease on endoscopic (77%) or histologic assessment only (80%). The specificity of endo/histologic inflammation for GI symptoms was < 65%. PRO-2 was positively correlated with endoscopic disease activity (Spearman's rank 0.57, 95% CI 0.54-0.60, p < 0.0001) and histologic disease activity (Spearman's rank 0.49, 0.45-0.53, p < 0.0001). CONCLUSION: One-quarter of patients with ulcerative colitis in endo-histologic (deep) remission have gastrointestinal symptoms, more commonly with diarrhea than rectal bleeding. Endo-histologic inflammation has high sensitivity (≥ 87%) for diarrhea/rectal bleeding.

Anti-Integrin αvß6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis.

BACKGROUND & AIMS: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvß6 (anti-αvß6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvß6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS: Anti-αvß6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvß6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvß6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS: Anti-αvß6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvß6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvß6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvß6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvß6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Dietary Habits and Nutrient Deficiencies in a Cohort of European Crohn's Disease Adult Patients.

Wrong dietary habits, such as the Western-style diet, are considered important risk factors for the development of Inflammatory Bowel Diseases (IBDs). Nevertheless, the role of dietary patterns in the clinical management of IBD patients has not been fully investigated yet. Fifty-four patients diagnosed with active Crohn's disease (CD) were enrolled and subjected to nutritional intake analysis through a weekly food diary. Nutritional patterns were analyzed, and nutrient intake was compared with those of 30 healthy subjects (HS). Blood levels of cholesterol, folic acid, minerals (K, Mg, Fe) and amino acids, were measured in CD patients to assess the presence of nutritional deficiencies. CD patients, with respect to HS, consumed significantly lower amounts of fiber, vitamins (A, E, C, B6, folic acid) and ß-carotene. Their calcium, potassium, phosphorus, iron, magnesium, copper and iodine intake were also found to be significantly lower. In blood, CD patients had significantly lower concentrations of total cholesterol, potassium, iron, and amino acids. Active CD patient diet was significantly different from those of HS and may contribute to the establishment of nutritional deficiencies. Intestinal malabsorption was evidenced in these patients. Correction of the diet with specific nutritional plans is a necessary therapeutic step for these patients. ClinicalTrials.gov: NCT02580864.

Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings's regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

Non-invasive Serological Monitoring for Crohn's Disease Postoperative Recurrence.

INTRODUCTION: Crohn's disease recurs after intestinal resection. This study evaluated accuracy of a new blood test, the Endoscopic Healing Index [EHI], in monitoring for disease recurrence. METHODS: Patients enrolled in the prospective POCER study [NCT00989560] underwent a postoperative colonoscopic assessment at 6 [2/3 of patients] and 18 months [all patients] following bowel resection, using the Rutgeerts score [recurrence ≥i2]. Serum was assessed at multiple time points for markers of endoscopic healing using the EHI, and paired with the Rutgeerts endoscopic score as the reference standard. RESULTS: A total of 131 patients provided 437 serum samples, which were paired with endoscopic assessments available in 94 patients [30 with recurrence] at 6 months and 107 patients [44 with recurrence] at 18 months. The median EHI at 6 months was significantly lower in patients in remission [Rutgeerts 

Erythrocyte complement receptor 1 (ECR1) and erythrocyte-bound C4d (EC4d) in the prediction of poor pregnancy outcomes in systemic lupus erythematosus (SLE).

BACKGROUND: Complement activation has been associated with adverse pregnancy outcomes (APO) in SLE. Pregnant women with SLE were studied to evaluate whether complement dysregulation within the first two pregnancy trimesters predicts APO. METHODS: Pregnant women fulfilled classification criteria for SLE. APO included neonatal death, preterm delivery before 36 weeks and small for gestational age newborn. Pre-eclampsia was also evaluated. Erythrocyte complement receptor 1 (ECR1) and erythrocyte-bound C4d (EC4d) were measured by flow cytometry. Complement proteins C3 and C4 were measured by immunoturbidimetry and anti-double-stranded DNA by ELISA in serum. Statistical analysis consisted of t-test, confusion matrix-derived diagnostic analysis, and multivariate logistic regression. RESULTS: Fifty-one women had 57 pregnancies and 169 visits during the study. Baseline visits occurred mainly in the first (n=32) and second trimester (n=21). Fourteen (24.6%) pregnancies resulted in 21 APO with preterm delivery being the most common (n=10). ECR1 <5.5 net mean fluorescence intensity in the first trimester predicted APO with a diagnostic OR (DOR) of 18.33 (95% CI: 2.39 to 140.4; t-test p=0.04). Other individual biomarkers did not reach statistical significance. To estimate the likelihood of APO, we developed an algorithm that included the week of pregnancy, ECR1 and EC4d. From this algorithm, a Pregnancy Adversity Index (PAI) was calculated, and a PAI >0 indicated an elevated likelihood of pregnancy complications (DOR: 20.0 (95% CI: 3.64 to 109.97)). CONCLUSIONS: Low levels of ECR1 in early or mid-pregnancy are predictive of an APO. Incorporating the weeks of gestation and both ECR1 and EC4d generated a PAI, which further predicted serious pregnancy complications.

Platelet bound complement split product (PC4d) is a marker of platelet activation and arterial vascular events in Systemic Lupus Erythematosus.

Platelet-bound complement activation products (PC4d) are associated with thrombosis in Systemic Lupus Erythematosus (SLE). This study investigated the effect of PC4d on platelet function, as a mechanistic link to arterial thrombosis. In a cohort of 150 SLE patients, 13 events had occurred within five years of enrollment. Patients with arterial events had higher PC4d levels (13.6 [4.4-24.0] vs. 4.0 [2.5-8.3] net MFI), with PC4d 10 being the optimal cutoff for event detection. The association of arterial events with PC4d remained significant after adjusting for antiphospholipid status, smoking, and prednisone use (p = 0.045). PC4d levels correlated with lower platelet counts (r = -0.26, p = 0.002), larger platelet volumes (r = 0.22, p = 0.009) and increased platelet aggregation: the adenosine diphosphate (ADP) concentration to achieve 50% maximal aggregation (EC50) was lower in patients with PC4d 10 compared with PC4d < 10 (1.6 vs. 3.7, p = 0.038, respectively). These results suggest that PC4d may be a mechanistic marker for vascular disease in SLE.

Performance Characteristics of a Clinical Decision Support Tool for Disease Complications in Crohn's Disease.

Background: Patients with Crohn's disease (CD) are at risk of complications. Performance characteristics of a decision support tool assessing the risk of CD complications were evaluated. Methods: CDPATH (formerly called the Personalized Risk and Outcome Prediction Tool [PROSPECT]) was calibrated and validated in 2 cohorts. Tool prediction of disease characteristics was assessed using Cox regression and Harrell's C-statistic. Results: All associations of CD complications and CDPATH components were significant except perianal location. There was a significant association between individualized risk assessment scores and CD complications in both cohorts. Conclusion: CDPATH is validated as a clinical decision support tool for assessing the risk of CD complications.

P010 Precision Dosing Tool Forecasts Trough Infliximab and Associates With Disease Status in Inflammatory Bowel Diseases.

BACKGROUND: Substantial inter- and intra-individual variability of infliximab (IFX) pharmacokinetics (PK) necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). METHODS: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. RESULTS: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/ml from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 =0.87. Observed end cycle and forecasted trough levels above 5µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7-30.2; OR = 21.0 CI95%: 3.4-127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/ml from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). CONCLUSION: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.