Predictive models assessing the response to ustekinumab highlight the value of therapeutic drug monitoring in Crohn's disease.

BACKGROUND: Despite the therapeutic efficacy of Ustekinumab (UST) in Crohn's disease (CD), loss of response (LOR) is observed over time. This study aims to evaluate the impact of the UST pharmacokinetics (PK) at induction on clinical and endoscopic outcomes, as well as to find predictive markers of UST response. METHODS: This retrospective study included 80 CD patients. Pharmacokinetics data (trough levels (TLs)) combined with clinical and biological parameters were fed into tailored logistic regression and tree-based ensemble techniques to predict clinical and endoscopic outcomes at one year of follow-up. RESULTS: TLs at week 16 were significantly lower among patients with moderate to severe endoscopic activity during the follow-up (p = 0.04). The best model to predict endoscopic outcome was obtained at week 16 by Random Forest with an area under the receiver operating characteristic curve of 0.92 ± 0.08, sensitivity 91% and specificity 75%, with key inputs such as lymphocyte and monocyte counts at week 8, and UST TLs and CRP at week 16. CONCLUSIONS: This real-world study confirms the relationship between early UST TLs and both clinical and endoscopic outcomes. Models were developed for the task of predicting clinical and endoscopic remission in CD patients treated with UST, highlighting the clinical relevance of UST TLs at week 16.

Crohn's disease-related 'gastrocnemius myalgia syndrome' successfully treated with infliximab: A case report.

BACKGROUND: Extra-intestinal manifestations in inflammatory bowel diseases (IBD) are frequent and involve virtually all organs. Conversely, the clinical characteristics and course of inflammatory myopathies in IBD remain poorly described and mostly related to orbital myositis. Moreover, alternative therapeutic strategies in non-responder patients to corticosteroid therapy must still be clarified. CASE SUMMARY: A 33-year-old woman with a history of unclassified colitis presented with acute bilateral calf pain. On admission, her clinical and biological examinations were non-specific. However, magnetic resonance imaging showed bilateral inflammatory changes in gastrocnemius muscles suggestive of myositis. Muscle biopsy confirmed the diagnosis of myositis and demonstrated an inflammatory infiltrate mainly located in the perimysial compartment including lympho-plasmocytic cells with the formation of several granulomatous structures while the endomysium was relatively spared. The combined clinical, biological and histomyopathological findings were concordant with the diagnosis of 'gastrocnemius myalgia syndrome' (GMS), a rare disorder associated with Crohn's disease (CD). Ileocolonoscopy confirmed CD diagnosis and systemic corticosteroids (CS) therapy was started, resulting in a rapid clinical improvement. During CS tapering, however, she experienced a relapse of GMS together with a severe active ileocolitis. Infliximab was started and allowed a sustained remission of both conditions at the latest follow-up (20 mo). CONCLUSION: The GMS represent a rare CD-associated inflammatory myopathy for which anti-tumour necrosis factor-α therapy might be considered as an effective therapeutic option.

Introduction of Subcutaneous Infliximab CT-P13 and Vedolizumab in Clinical Practice: A Multi-Stakeholder Position Statement Highlighting the Need for Post-Marketing Studies.

BACKGROUND AND AIMS: Although subcutaneous formulations of infliximab CT-P13 and vedolizumab are registered for treating moderate-to-severe inflammatory bowel disease [IBD], many questions on their use remain unanswered. We set up a multi-stakeholder initiative resulting in a position statement. METHODS: Based on publicly available data, statements on subcutaneous infliximab and vedolizumab were developed and reviewed by 45 Belgian IBD physicians in a three-round modified Delphi process. During a consensus meeting, input from 16 IBD patients, nine IBD nurses and two clinical pharmacologists was provided and statements were further discussed, modified and scored. Statements achieving agreement by at least 70% of the IBD physicians were accepted. RESULTS: The Delphi process resulted in 79 agreed statements. In patients initiating intravenous therapy, IBD physicians would only consider switching to subcutaneous formulations in patients achieving both clinical and biological response [for Crohn's disease] or both clinical and endoscopic response [for ulcerative colitis]. For patients under maintenance therapy, switching to subcutaneous formulations was only considered in those achieving both clinical and endoscopic response while receiving standard dosing of infliximab or vedolizumab. While awaiting more scientific data, IBD physicians should consider weekly subcutaneous injections or switching back to an intravenous formulation in case of loss of response. Finally, switching to a subcutaneous formulation should always be a shared decision. CONCLUSIONS: All stakeholders welcomed subcutaneous infliximab and vedolizumab. However, more scientific data are needed to select the right patients and timing for switching to these newer formulations, and to explore the optimal strategy in case of loss of response.

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases.

BACKGROUND: The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS: This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS: Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ±â€…0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS: This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.

Effectiveness of Third-Class Biologic Treatment in Crohn's Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn's disease (CD) failing anti- Tumor necrosis factors (TNFs); however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described. AIMS AND METHODS: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD. RESULTS: Two-hundred and four patients were included; 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A); the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16-22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9); 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52; 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9); 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5). CONCLUSION: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.

New approach to determine the healthy immune variations by combining clustering methods.

Immune-mediated inflammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defining the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their influencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefficients of variation confirmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors affected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some influence of age, gender, BMI, cortisol, season and CMV infection on immune variability.

Switching biologics used in inflammatory bowel diseases: how to deal with in practice?

Inflammatory bowel disease patients do not all respond to biological treatment since several patients will initially respond but will lose response or develop side effects over time. In such cases, a switch from one biologic to another offers a valuable clinical solution. This requires to evaluate both patient and drug profiles in combination with the reason(s) for switching in order to adequately select the second-line biologic. Therapeutic drug monitoring is obviously a useful tool but is currently limited to the use of anti-TNFα. In this review paper, we provide overview and guidance on switching biologics in clinical practice, with the emphasis on the motivations for switching, the selection of the second-line biologic, as well as explanations on how and when to switch.

Effectiveness of ustekinumab dose escalation in Crohn's disease patients with insufficient response to standard-dose subcutaneous maintenance therapy.

BACKGROUND: Ustekinumab is effective in Crohn's disease. However, a substantial proportion of patients will not respond or lose response to ustekinumab. The current evidence to support the effectiveness of dose-optimisation for ustekinumab nonresponse is limited. AIM: To assess the effectiveness of dose escalation of ustekinumab. METHODS: This was a multicentre retrospective cohort study. We included active Crohn's disease patients who received a standard-dose intravenous induction and at least one subcutaneous ustekinumab 90 mg dose. All enrolled patients received dose escalation by either shortening the interval between the doses to every 4 or 6 weeks, intravenous reinduction or a combination of strategies. The primary outcome of the study was clinical response at week 16 after dose escalation. RESULTS: A total of 142 patients (22 centres/14 countries) were included. The patients were dose-escalated after a median treatment duration of 30 weeks. At week 16 from escalation, 73/142 (51.4%) responded to treatment, including 55/142 (38.7%) in clinical remission. Corticosteroid-free remission was achieved in 6/34 (17.6%) patients on corticosteroids at the time of escalation; 118/142 (83%) continued treatment beyond week 16. Follow-up data beyond week 16 were available for 74/118 (62.7%) patients. On the last follow-up, 51/98 (52%) patients with available data responded to treatment, including 41/98 (42%) in clinical remission. CONCLUSIONS: Intensification of ustekinumab maintenance dosage was effective in over 50% of the patients. This strategy should be considered in patients who are nonresponsive to every 8 weeks ustekinumab maintenance dosing.

New insights in acetaminophen toxicity: HMGB1 contributes by itself to amplify hepatocyte necrosis in vitro through the TLR4-TRIF-RIPK3 axis.

Extracellular release of HMGB1 contributes to acetaminophen-induced liver injury. HMGB1 acts as a danger-associated molecular patterns during this toxic process but the mechanisms of action and targeted cells are incompletely defined. Here we studied, in vitro, the role of HMGB1 in amplifying the acetaminophen-induced hepatocyte necrosis process. Using cultured HepaRG cells, primary human hepatocytes and selective chemical inhibitors we evaluated acetaminophen-induced toxicity. We confirmed that addition of acetaminophen induced HepaRG cell death and HMGB1 release. We showed that inhibition of HMGB1 decreased acetaminophen-induced HepaRG cell death, suggesting a feedforward effect. We provide the first evidence that exposure of HepaRG cells to recombinant human HMGB1 (rhHMGB1) also resulted in cell death. Moreover, we found that both acetaminophen and rhHMGB1 induced programmed HepaRG cell necrosis through a RIPK3-dependent mechanism. By using TLR4 blocking antibody, we demonstrated the reduction of the HepaRG cell death induced by acetaminophen and rhHMGB1. Furthermore, inhibition of TRIF, known to induce a RIPK3-dependent cell death, reduced rhHMGB1-induced HepaRG cell death. Our data support that released HMGB1 from acetaminophen-stressed hepatocytes induced necrosis of neighboring hepatocytes by TLR4-TRIF-RIPK3- pathway. This in vitro study gives new insights in the role of HMGB1 in the amplification of acetaminophen-induced toxicity.

Impact of first-line infliximab on the pharmacokinetics of second-line vedolizumab in inflammatory bowel diseases.

Background: Very little is known about the impact of the wash-out period on the pharmacokinetics of a second-line biologic. Objective: The objective of this article is to explore the impact of two different wash-out periods on the pharmacokinetics of vedolizumab and infliximab. Methods: Patients switching from infliximab to vedolizumab were retrospectively identified. The population was divided into two groups according to wash-out period: <6 weeks or >6 weeks. Vedolizumab and infliximab trough levels (TLs) were determined and correlated with clinical and biological outcomes. Results: A total of 71 inflammatory bowel disease patients were included. At week 6, in patients previously treated with infliximab, median vedolizumab TLs were 21.9 µg/ml and 24.9 µg/ml for the <6 weeks and >6 weeks wash-out period, respectively (p = 0.31), whereas median residual infliximab TLs were 0.5 µg/ml and 0 µg/ml (p = 0.034). The rate of treatment discontinuation was similar (p = 0.64), and the infectious events were six and two for the <6 weeks and >6 weeks wash-out period, respectively (p = 0.12) by week 30. Conclusions: This study suggests clinicians may not need to be concerned about the impact of wash-out period on the pharmacokinetics of the second-line biologic when switching infliximab to vedolizumab. More data are required on the impact of wash-out period on safety.

Variability of Faecal Calprotectin in Inflammatory Bowel Disease Patients: An Observational Case-control Study.

BACKGROUND AND AIMS: Several factors have been reported to affect faecal calprotectin [FC] values, and significant variation in FC concentrations has been observed in inflammatory bowel disease [IBD] patients. We aimed to evaluate FC variability in IBD patients, and to assess the robustness of a single stool punch. METHODS: This is a single-centre observational case-control study. Disease activity was assessed using endoscopic and clinical activity scores, as well as C-reactive protein levels. Stool samples were collected twice within a 1 to 6 days interval, and FC was measured on punches and homogenates by fluorometric enzyme immunocapture assay. RESULTS: In all, 260 stool samples were collected from 120 patients. Intrastool variability was low, with an intraclass correlation coefficient for single measures between three punches from a single stool sample of 0.91, and median coefficient of variation [CV] of 17%. CV of two stool samples a few days apart [intra-individual variability] were significantly higher [p <0.01] with median CV of 36%. FC standard deviations correlated with mean FC levels either for intrastool or for intra-individual variability, with a Spearman's coefficient of rank correlation of 0.85 and 0.78, respectively [p <0.01]. Disease type, location, activity, and FC levels did not influence variability. CONCLUSIONS: A single stool punch is reliable for FC measurement, considering that intrastool variability is low. Intra-individual variability a few days apart is significantly higher. Therefore, decision-making strategies based on single measurements should consider this variability, to determine the minimum optimal variation to be achieved, rather than a cut-off, especially in high FC levels.

Long-term Clinical Effectiveness of Ustekinumab in Patients with Crohn's Disease Who Failed Biologic Therapies: A National Cohort Study.

BACKGROUND: Ustekinumab [UST] was recently approved in Europe for the treatment of moderate to severe Crohn's disease [CD]. Long-term real-world data are currently scarce for CD patients previously exposed to several biologics. METHODS: This is an observational, national, retrospective multicentre study. Patients received intravenous UST ~6 mg/kg at baseline, with 90 mg subcutaneously thereafter every 8 weeks. Response and remission rates were assessed at Weeks 8, 16, and 52. RESULTS: Data from 152 patients were analysed. All patients were exposed to at least one anti-TNFα agent, with 69.7% were exposed to even two anti-TNFα and vedolizumab. After 1 year, 42.1% and 25.7% of patients had experienced clinical response and clinical remission, respectively, and 38.8% and 24.3% had achieved steroid-free clinical response and remission, respectively; 38.8% of patients discontinued therapy during the 12 months of follow-up. Colonic location was predictive of clinical response at 1 year, and low body mass index [BMI] at baseline was a negative predictor of clinical remission. Resolution of arthralgia was associated with clinical response over time. De novo arthralgia was reported by 17.9% of patients at Week 8 and 13.5% of patients at Week 52. No impact of UST on arthralgia was observed in patients with concomitant ankylosing spondylitis [n = 17]. Others adverse events were reported in 7.2% of patients. CONCLUSIONS: This real-world cohort study confirms the effectiveness of UST in CD patients previously exposed to several biologics. Ustekinumab was well tolerated with respect to adverse events. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance.

BACKGROUND: Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. OBJECTIVE: The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. PATIENTS AND METHODS: This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. RESULTS: During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. CONCLUSION: We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.

Viewpoint: Toward the Genetic Architecture of Disease Severity in Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) is characterized by uneven disease courses with various clinical outcomes. A few prognostic markers of disease severity may help stratify patients and identify those who will benefit the most from early aggressive treatment. The concept of disease severity remains too broad and vague, mainly because the definition must embrace several disease mechanisms, mainly inflammation and fibrosis, with various rates of disease progression. The magnitude of inflammation is an obvious key driver of disease severity in IBD that ultimately influence disease behavior. Advances in the genetics underlying disease severity are currently emerging, but attempts to overlap the genetics of disease susceptibility and severity have until now been unsatisfactory, suggesting that the genetic architecture of disease severity may be distinct from the genetics of disease susceptibility. In this review, we report on the current knowledge on disease severity and on the main research venues to decipher the genetic architecture of disease severity.

Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.

Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance.

BACKGROUND: Infliximab (IFX) is indicated for the treatment of inflammatory bowel diseases (IBD). Nevertheless, loss of response (LOR) to IFX is reported in up to 10% to 30% of patients within the first year of treatment. Our objective was to evaluate the impact of the pharmacokinetics of IFX at induction on treatment failure. METHODS: This is a longitudinal cohort study on 269 patients with IBD treated with IFX in a single center. A total of 2331 blood samples were prospectively collected from 2007 until March 2015 with a retrospective analysis of clinical data. IFX trough levels (TLs) were measured by enzyme-linked immunosorbent assay. Antibodies to IFX were measured by drug-sensitive bridging assay. RESULTS: During follow-up, patients were defined according to treatment outcome. At week 6, median IFX TL in patients requiring a switch to another treatment due to LOR (LOR switched group) (2.32 µg/mL [0.12-19.93 µg/mL]) was lower than in patients with long-term response (long-term responders) (8.66 µg/mL [0.12-12.09 µg/mL], P = 0.007) and in patients responding to optimization (LOR optimized group) (7.28 µg/mL [0.17-14.91 µg/mL], P = 0.021). At week 2, median IFX TL was lower in the LOR switched group (5.7 µg/mL [0.15-12.09 µg/mL]) compared with the long-term responders (11.92 µg/mL [0.14-19.93 µg/mL], P = 0.041) but no significant difference was reached with the LOR optimized group (11.91 µg/mL [0.23-12.09 µg/mL], P = 0.065). In the LOR switched group, median IFX TL at induction (weeks 2 and 6) was significantly lower when patients had been previously exposed to anti-tumor necrosis factor compared with naive patients (0.91 µg/mL [0.12-4.4 µg/mL] versus 6.6 µg/mL [0.15-19.93 µg/mL], P = 0.044). CONCLUSIONS: This study suggests that patients who do not respond to any optimization strategy have lower IFX TLs during induction at week 6. IFX TLs measured early on at induction might predict treatment failure to IFX during maintenance.