‘Treat to Target' - Lessons Learnt

2016 ◽  
Vol 34 (1-2) ◽  
pp. 147-152 ◽  
Author(s):  
Zsuzsanna Kurti ◽  
Zsuzsanna Vegh ◽  
Petra Anna Golovics ◽  
Peter Laszlo Lakatos

Background: Therapeutic management in inflammatory bowel diseases (IBD) has significantly changed in the last decades with the advent of biological therapy resulting in new treatment targets other than clinical symptoms. Key Messages: Patient stratification in the early stage of the disease is an important step to identify patients with poor prognosis, who might benefit from early aggressive treatment to avoid complications in the later disease course. Recent randomized and hypothesis driven (e.g., Randomized Evaluation of an Algorithm for Crohn's Treatment, Post-Operative Crohn's Endoscopic Recurrence) clinical trials conducted in the biological era underscore the need of objective disease monitoring including assessment of biomarkers (e.g., C-reactive protein and calprotectin), mucosal healing and, for biologically treated patients, therapeutic drug monitoring beside clinical symptom assessment in both Crohn's disease and ulcerative colitis. Conclusions: Assessing the treatment efficacy objectively has become an important element of patient monitoring besides clinical symptom assessment. Further clinical studies are needed to assess whether implementation of new therapeutic algorithms based on these targets and tight monitoring in clinical practice have the potential to further improve long-term disease outcomes in IBD.

2019 ◽  
Vol 14 (2) ◽  
pp. 254-266 ◽  
Author(s):  
Jean-Frédéric Colombel ◽  
Geert D’haens ◽  
Wan-Ju Lee ◽  
Joel Petersson ◽  
Remo Panaccione

Abstract Background and Aims Management of Crohn’s disease and ulcerative colitis has typically relied upon treatment intensification driven by symptoms alone. However, a ‘treat-to-target’ management approach may help to address underlying inflammation, minimise disease activity at early stages of inflammatory bowel disease, limit progression, and improve long-term outcomes. Methods A systematic literature review was conducted to identify data relevant to a treat-to-target approach in inflammatory bowel disease, published between January 1, 2007 and May 15, 2017. Results Consistent with recommendations of the Selecting Therapeutic Targets in Inflammatory Bowel Disease [STRIDE] working group, studies have investigated factors influencing the achievement of both endoscopic and histological mucosal healing and patient-level outcomes in inflammatory bowel disease [IBD]. Histological healing and biomarker levels have also been shown to be modifiable outcomes. Although there is a lack of prospectively derived evidence validating mucosal healing as a treatment target, data are emerging to suggest that targeting mucosal healing or inflammation rather than symptoms may be cost-effective in some settings. The review highlighted several strategies that may support the implementation of a treat-to-target approach in IBD. The prospective randomised CALM study demonstrated how tight control [whereby treatment decisions are based on close monitoring of inflammatory biomarkers] leads to improvements in endoscopic and clinical outcomes. The review also considered the influence of coordinated care from a multidisciplinary team and patient engagement with improved adherence, as well as the role of therapeutic drug monitoring in inflammatory bowel disease management. Conclusions A treat-to-target strategy may impact on disease progression and improve outcomes in inflammatory bowel disease. Prospective studies including long-term data are required to ensure that the most appropriate targets and strategies are identified.


2019 ◽  
Vol 57 (12) ◽  
pp. 1906-1914 ◽  
Author(s):  
Emilio J. Laserna-Mendieta ◽  
Sara Salvador-Martín ◽  
Laura Arias-González ◽  
Miriam Ruiz-Ponce ◽  
Luis A. Menchén ◽  
...  

Abstract Background Therapeutic drug monitoring (TDM) of adalimumab (ADA) in inflammatory bowel diseases (IBDs) has gained increased attention since several studies showed a correlation between drug levels and mucosal healing. The limitations of routine usage of enzyme-linked immunoabsorbent assay (ELISA) kits for measuring serum ADA concentrations have prompted the development of rapid methods, such as Quantum Blue (QB). We evaluated the interchangeability and agreement between the QB method and two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). Methods Fifty samples from patients with IBD were included. Quantitative analysis was performed using the ANOVA test for repeated measures, Deming regression and the Bland-Altman plot. Clinical implications were evaluated by concordance in classifying patients into therapeutic windows according to the proposed cut-off levels for subtherapeutic (either <5 or <7.5 μg/mL) and supratherapeutic (>12 μg/mL) ranges. Results Statistical differences were detected between the QB method and the two ELISA kits, with QB overestimating ADA serum values compared to them. A lack of interchangeability was observed between methods, with greater differences as ADA levels increased. An analysis of a sub-set of samples with ADA values below 9 μg/mL (n = 25) showed that QB fulfilled the criteria to be interchangeable with the LT assay. Concordance for patient classification into ADA therapeutic windows was better for QB vs. LT than for QB vs. PM, with high agreement (>75%) for subtherapeutic levels among the three methods. Conclusions Although quantitative differences existed between the rapid method and ELISA kits that hampered their interchangeability, the agreement for identifying patients with subtherapeutic values of ADA was high.


2022 ◽  
Vol 12 ◽  
Author(s):  
Yujiao Lai ◽  
Hori Masatoshi ◽  
Yanbo Ma ◽  
Yuming Guo ◽  
Bingkun Zhang

Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC) generally characterized by clinical symptoms, including malabsorption, intestinal dysfunction, injury, and microbiome imbalance, as well as certain secondary intestinal disease complications, continue to be serious public health problems worldwide. The role of vitamin K (VK) on intestinal health has drawn growing interest in recent years. In addition to its role in blood coagulation and bone health, several investigations continue to explore the role of VK as an emerging novel biological compound with the potential function of improving intestinal health. This study aims to present a thorough review on the bacterial sources, intestinal absorption, uptake of VK, and VK deficiency in patients with intestinal diseases, with emphasis on the effect of VK supplementation on immunity, anti-inflammation, intestinal microbes and its metabolites, antioxidation, and coagulation, and promoting epithelial development. Besides, VK-dependent proteins (VKDPs) are another crucial mechanism for VK to exert a gastroprotection role for their functions of anti-inflammation, immunomodulation, and anti-tumorigenesis. In summary, published studies preliminarily show that VK presents a beneficial effect on intestinal health and may be used as a therapeutic drug to prevent/treat intestinal diseases, but the specific mechanism of VK in intestinal health has yet to be elucidated.


Author(s):  
Claire Liefferinckx ◽  
Jérémie Bottieau ◽  
Jean-François Toubeau ◽  
Debby Thomas ◽  
Jean-François Rahier ◽  
...  

Abstract 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 ± 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.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christoph Kessel ◽  
Miha Lavric ◽  
Toni Weinhage ◽  
Markus Brueckner ◽  
Sytze de Roock ◽  
...  

AbstractCrohn's disease (CD) and ulcerative colitis (UC) have a chronic-remittent course. Optimal management of inflammatory bowel diseases (IBD) relies on early intervention, treat-to-target strategies and a tight disease control. However, it is challenging to assess the risk of relapses in individual patients. We investigated blood-based biomarkers for the confirmation of disease remission in patients with IBD. We retrospectively analyzed samples of 40 IBD patients (30 UC, 10 CD) enrolled in a tight-control follow-up study. Half of the patients had a flare during follow up. Serum was analyzed for S100A12 as well as S100A8/A9 and for 50 further biomarkers in a bead-based multiplex assay. The concentrations of 9 cytokines/chemokines and S100A8/A9 significantly differed in IBD patients with unstable remission (before flares) when compared to IBD patients with stable remission. Although the number of patients was small, ROC curve analyses revealed a number of biomarkers (IL-1β, IL-1RA, IL-8, IL13, IL-15, IL-21, IL-25, IFN-β, CXCL9, CXCL10, CXCL11, Galectin-1, G-CSF and S100A8/A9) that were elevated in patients with later occurring relapses. While earlier studies on peripheral biomarkers in IBD are limited to only few analytes, our study using a broad screening approach identified serum biomarkers with the potential to indicate unstable disease control in IBD, which may help to steer individual therapies to maintain remission.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Si ◽  
Mohamed Kazamel ◽  
Michael Benatar ◽  
Joanne Wuu ◽  
Yuri Kwon ◽  
...  

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.


2021 ◽  
pp. 197140092110269
Author(s):  
Prateek Gupta ◽  
Sameer Vyas ◽  
Teddy Salan ◽  
Chirag Jain ◽  
Sunil Taneja ◽  
...  

Background and purposes Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. Materials and methods Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). Results The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (–0.52 to –0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. Conclusion DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1306.1-1306
Author(s):  
P. Tremaskina ◽  
E. Loginova ◽  
T. Korotaeva ◽  
S. Glukhova ◽  
A. Lila

Background:The concept of treat to target (T2T) in psoriatic arthritis (PsA) has been established recently and already shown its benefits [1]. But the long-term outcomes of the T2T have not been studied yet.Objectives:To study 5 years (yrs) follow-up of PsA patients (pts) treated according to T2T strategy at the early stage.Methods:35 (M/F–17/18) PsA pts fulfilling CASPAR criteria, who were treated according to T2T strategy at the early stage (PsA duration≤2 yrs) within 24 months (mos) were analyzed. At the time of evaluation mean age is 42.7±11.2 yrs, median (Me) PsA duration 72 [60;95] mos, psoriasis duration 120 [88;180] mos. All pts underwent standard clinical examinations of PsA before started T2T therapy and at follow-up. Within 24 mos of T2T strategy all pts were taking Methotrexate (MTX) monotherapy in increasing dose up to 25 mg/wk and 18 out of 35 (51%) pts received MTX in combination with iTNF. When T2T study was stopped all pts were treated according to standard care with NSAIDs, bDMARDs, MTX, tsDMARDs based on PsA activity and physician decision. The number of pts achieved minimal disease activity (MDA, 5 of 7) and remission by DAPSA (≤4)/low disease activity (LDA)≤14) at the 24 mos of T2T strategy and at 5 yrs follow-up were calculated. The results are presented in the form of mean values, median, upper and lower quartiles.Results:Me duration of follow-up is 68 [53.5;81.5] mos. At 24 mos Me DAPSA 3.48 [0.45;21.76], remission by DAPSA (REM-DAPSA) were seen in 20 out of 35 (57%) pts, LDA-DAPSA in 4 (12%) pts, moderate activity (MoA) by DAPSA in 6 (17%) pts and high disease activity by DAPSA (HDA-DAPSA) in 5 (14%) pts. MDA was noted in 21 out of 35 (60%) pts. At 5 yrs Me DAPSA 7.4 [2.22;13.87], REM-DAPSA was noted in 12 (34%) pts, LDA-DAPSA in 14 (40%), MoA-DAPSA in 5 (14%), HDA-DAPSA in 4 (12%) pts. MDA was observed in 17 of 35 pts (49%). Among 20 pts who had REM-DAPSA at 24 mos only 6 pts (30%) remained in remission at 5 yrs follow-up and 12 out of 21 pts (57.14%) remained in MDA status.Conclusion:In early PsA pts remission and MDA are achievable goal of T2T strategy. But most pts lost remission/MDA after this strategy was changed to a standard care, despite being in remission/MDA status before change of therapy. Further investigations of the long-term outcomes of T2T strategy in PsA, including radiographic outcomes are needed.References:[1]Coates LC, Moverley AR, McParland L, et al. Lancet 2015; 386: 2489–98.Disclosure of Interests:None declared.


2003 ◽  
Vol 285 (3) ◽  
pp. G556-G565 ◽  
Author(s):  
C. Linard ◽  
A. Ropenga ◽  
M. C. Vozenin-Brotons ◽  
A. Chapel ◽  
D. Mathe

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal γ-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1β, TNF-α, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-β (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1β ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-κB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-κB (p65, p50) and AP-1 (c- fos, c- jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.


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