High anti-TNF alfa drugs trough levels are not associated with the occurrence of adverse events in patients with inflammatory bowel disease.

Objectives: Up to 40% of inflammatory bowel disease (IBD) patients treated with anti-TNF drugs lose response within 1 year of treatment, therefore requiring drug optimization. Although higher drug trough levels (TLs) are associated with sustained clinical outcomes, there are concerns that they may be associated with a higher risk of adverse events (AEs). The aim was to evaluate the presence of a possible association between drug TLs and the occurrence of AEs in IBD patients treated with anti-TNF drugs.Methods: We retrospectively studied a cohort of 113 IBD patients treated with adalimumab or infliximab, of whom 27 were in combination therapy with immunosuppressants. TLs were measured using a homogeneous mobility shift assay.Results: During a median follow-up of 16 months (range 1-144), we observed 103 AEs occurring in 58 patients. We found no statistically significant difference (p = .21) in median TLs between patients who did 6.7 mcg/mL; range 0.0-36.2) or did not (7.7 mcg/mL; range 0.0-20.7) experience an AE. No difference was observed in the rate of AEs between patients in mono- or combination therapy (p = .38), as well as between elderly (i.e., >65 years) and younger patients (p = .32). Considering a TL cutoff of 7 mcg/mL for infliximab and 12 mcg/mL for adalimumab, or even double these TL values, we observed no statistically significant difference in the rate of AEs occurrence.Conclusion: Our study suggests that, when clinically required, anti-TNF drug dosage may be increased without particular concerns regarding the risk of AEs occurrence in IBD patients, even in patients on combination therapy and elderly ones.

Reduction in TIMP-2 serum levels predicts remission of inflammatory bowel diseases.

BACKGROUND: Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. MATERIAL & METHODS: In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-α antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and -8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. RESULTS: The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. CONCLUSIONS: This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-α antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified.

Adalimumab trough serum levels and anti-adalimumab antibodies in the long-term clinical outcome of patients with Crohn's disease.

OBJECTIVE: Few data are available on the relevance of adalimumab (ADA) trough serum levels and anti-ADA antibodies (AAA) during long-term follow-up of patients with Crohn's Disease (CD), and their association with disease outcome. In this study, our aim was to assess ADA trough serum levels and the presence of AAA according to disease activity and clinical response during long-term follow-up in a series of patients with CD treated with ADA monotherapy. MATERIAL AND METHODS: We prospectively evaluated 23 consecutive, infliximab-naïve CD patients who achieved clinical remission/response after induction and were in maintenance treatment with ADA, and who were followed-up for at least 72 weeks. Blood samples were drawn at standardized time points to assess ADA through levels, AAA. RESULTS: At week 48, we found significantly (p = 0.027) different ADA trough serum levels in patients in remission (10.1 mcg/mL), mild (7.4 mcg/mL), and moderate/severe disease (4.5 mcg/mL). Median ADA trough levels were significantly lower in patients with AAA (3.7 mcg/mL versus 9.3 mcg/mL, p = 0.006). At the end of follow-up (median 102 weeks, range 73-112 weeks), ADA trough serum concentrations were significantly higher (11.9 mcg/mL) as compared to patients with mild and moderate/severe disease (5.5 mcg/mL, p = 0.0002). Furthermore, median ADA trough concentrations showed a trend towards lower levels in AAA positive patients (5.2 mcg/mL versus 7.2 mcg/mL, p = 0.371). CONCLUSIONS: Our results emphasize the relevance of therapeutic drug monitoring in CD patients on biologic treatment. ADA trough serum levels and the presence of AAA are important features in the management of patients on ADA treatment.

Therapeutic drug monitoring in Crohn's disease patients treated with anti-TNF: a comparison of two techniques.

BACKGROUND: Therapeutic drug monitoring is a useful clinical decision aid in managing patients with inflammatory bowel disease treated with anti-tumor necrosis factor (anti-TNF). Various techniques are available to evaluate drug trough levels, and among these a point-of-care (POC) method has been proposed to overcome the limitations inherent to other methodologies. In this study we aimed to evaluate the capability of POC to discriminate between relapse and remission disease phases, and to assess the concordance of the POC and homogeneous mobility shift assay (HMSA) results. METHODS: Drug trough level of 46 Crohn's disease patients treated with either adalimumab or infliximab were evaluated with both a POC technique and an HMSA at various time points (week-16 and -48) during anti-TNF treatment. RESULTS: Median adalimumab trough level of patients in remission were significantly higher as compared to relapsing patients using both HMSA (week 16, P = 0.0001; week48, P = 0.001) and POC (week 16, P = 0.0003; week 48, P = 0.0012), and similar results were observed with infliximab trough level at week 16 (HMSA, P = 0.019; POC, P = 0.0072). Overall, we observed a good correlation between the techniques for both infliximab (r = 0.76; P < 0.0001) and adalimumab (r = 0.75; P < 0.0001), with no difference in discriminatory accuracy between assays (infliximab: HMSA versus POC c-index, 0.921 versus 0.895, P =0.149; adalimumab: HMSA versus POC c-index, 0.817 versus 0.850, P = 0.197). CONCLUSION: Both POC and HMSA assays are able to reliably differentiate relapse and remission phases in Crohn's disease patients treated with anti-TNF. These techniques showed good concordance and we feel that their preferential use should be based on local accessibility, physicians' experience and preference, and the need for timeliness availability of results.

Hepatic Elastometry and Glissonian Line in the Assessment of Liver Fibrosis.

The aim of this study was to identify a method for staging hepatic fibrosis using a non-invasive, rapid and inexpensive technique based on ultrasound morphologic hepatic features. A total of 215 patients with different liver diseases underwent B-mode (2-D brightness mode) ultrasonography, vibration-controlled transient elastography, 2-D shear wave elastography and measurement of the controlled attenuation parameter with transient elastography. B-Mode images of the anterior margin of the left lobe were obtained and processed with automatic Genoa Line Quantification (GLQ) software based on a neural network for staging liver fibrosis. The accuracy of GLQ was 90.6% during model training and 78.9% in 38 different patients with concordant elastometric measures. Receiver operating characteristic curve analysis of GLQ performance using vibration-controlled transient elastography as a reference yielded areas under the curves of 0.851 for F ≥ F1, 0.793 for F ≥ F2, 0.784 for F ≥ F3 and 0.789 for F ≥ F4. GLQ has the potential to be a rapid, easy-to-perform and tolerable method in the staging of liver fibrosis.

Cost per care of the first year of direct antiviral agents in the Liguria Region: a multicenter analysis.

AIMS: Despite the remarkable efficacy shown in clinical practice, concerns have been raised about the costs associated with direct antiviral agent (DAA) therapy. This article presents the real-life costs for DAA treatment sustained by the Italian National Health Service in the Liguria Region (Northern Italy). METHODS: A retrospective analysis of the cost per care sustained for DAA treatment, relating to the period from January 1 to December 31, 2015 in five centers in Liguria was performed. All patients undergoing DAA-based treatments for hepatitis C virus (HCV) infection were enrolled. On-treatment costs included: HCV treatment, laboratory test, outpatient services, attended visits, drugs used for the management of adverse events (erythropoietin, albumin or red blood cell packs) and inpatient service admissions. RESULTS: In total, 327 patients were enrolled. No difference in terms of sustained virologic response (SVR) rate among different treatments was reported. The majority (85.0%) of patients did not report any side effects and only 15 (4.6%) required hospital admission. Forty-two patients (12.8%) required high-cost drugs for the management of adverse events. The overall cost sustained was €14,744,433. DAA±ribavirin (RBV) accounted for the wide majority of this cost (98.9%; €14,585,123). Genotype (GT) 1, the most commonly treated GT, was associated with an average cost of €43,445 per patient. Detailed analysis of the costs for GT 1 showed the treatment based on ritonavir boosted paritaprevir/ombitasvir + dasabuvir±RBV with an average cost of €24,978 (RBV+) and €25,448 (RBV-) per patient was the most cost-effective. The average cost per SVR was €48,184. Once again, the ritonavir boosted paritaprevir/ombitasvir + dasabuvir regimen was associated with the lowest cost/SVR (€25,448/SVR [GT 1b] and similar results for other GTs). CONCLUSION: Antiviral regimen is the major contributor to costs in the treatment of HCV infection. Appropriate regimen selection could result in a major cost saving, which can be reinvested to allow more patients to be treated.

Comparison of Two Different Techniques to Assess Adalimumab Trough Levels in Patients with Crohn's Disease.

BACKGROUND AND AIMS: Loss of response to anti-tumor necrosis factor (TNF) drugs in patients with inflammatory bowel disease is likely due to low drug serum levels, and dosing anti-TNF drug concentrations may improve patients' outcome. However, there are limited data on the diagnostic accuracy and utility of currently available assays for measuring anti-TNF levels. In this study, our aim was to compare serum adalimumab concentrations with two different techniques. METHODS: We assessed serum adalimumab concentrations in 23 patients with Crohn's disease during a 96-week follow-up period. Adalimumab trough levels were assessed using a sandwich principle-based enzyme-linked immunosorbent assay (ELISA) and a homogeneous mobility shift assay (HMSA). RESULTS: At week 48, adalimumab trough levels were significantly lower in patients who experienced relapse compared to patients in remission, using both ELISA and HMSA methods: 4.8 mcg/mL (2.4-7.2 mcg/mL) vs. 7.5 mcg/mL (6.6-8.4 mcg/mL) (P=0.01) and 6.5 mcg/mL (3-10 mcg/mL) vs. 11.6 mcg/mL (7-16.2 mcg/ml) (P=0.004), respectively. Similar results were obtained at week 96: 5.9 mcg/mL (3.3-8.5 mcg/mL) vs. 12.8 mcg/mL (9.4-16.2 mcg/mL) (P=0.001) and 4.1 mcg/mL (1.6-6.6 mcg/mL) vs. 7.5 mcg/mL (5.7-9.3 mcg/mL) (P=0.009), respectively. There was a significant correlation between ELISA and HMSA adalimumab trough levels at both 48 (r = 0.691, P=0.0003) and 96 week (r = 0.822, P=0.0001). CONCLUSIONS: ELISA and HMSA assays are accurate methods to assess adalimumab trough levels in patients with Crohn's disease and those who experience loss of response. The preferential use of one of the two techniques should be based on local availability and physicians' experience.

Low serum trough levels are associated with post-surgical recurrence in Crohn's disease patients undergoing prophylaxis with adalimumab.

BACKGROUND: Whether therapeutic drug monitoring of biologic therapy can predict the efficacy of adalimumab to prevent postoperative Crohn's disease recurrence is unknown. AIM: To investigate whether adalimumab trough levels and anti-adalimumab antibodies correlate with endoscopic and clinical outcomes in a series of patients treated with prophylactic adalimumab monotherapy after resective surgery. METHODS: Post hoc analysis of a randomized, mesalamine-controlled trial. Adalimumab trough levels and antibodies were analysed every 8 weeks for 2 years using an homogeneous mobility shift assay. RESULTS: At two years, 1/6 patient had clinical recurrence and 1/6 patient had endoscopic and clinical recurrence. At baseline (9.5 vs. 14.4 mcg/mL) and during follow-up [7.5 (4.4-9.8) vs. 13.9 (8.9-23.6)mcg/mL, p<0.01], median adalimumab trough levels in patients with clinical or endoscopic recurrence were lower than in those who maintained remission. Persistent antibodies-against-adalimumab were detected in the patient with both endoscopic and clinical recurrence. CONCLUSION: Measurement of adalimumab trough levels and anti-adalimumab antibodies after surgery could be useful to further reduce postoperative recurrence.