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Projeto de investigação
Novo título: “Anti-drug Antibodies” Anti-TNF pharmacokinetics: In vitro model
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Serum dipeptidyl peptidase 4 : a predictor of disease activity and prognosis in inflammatory bowel disease
Publication . Pinto Lopes, Pedro; Afonso, Joana; Pinto Lopes, Rui; Rocha, Cátia; Lago, Paula; Gonçalves, Raquel; Tavares de Sousa, Helena; Macedo, Guilherme; Camila Dias, Cláudia; Magro, Fernando
Background: Serum dipeptidyl peptidase 4 (DPP-4) has drawn particular interest as a biomarker in inflammatory bowel disease (IBD), as this protease inactivates several peptides that participate in the inflammatory cascade. Methods: Two prospectively recruited cohorts consisting of 195 patients (101 had Crohn’s disease [CD] and 94 had ulcerative colitis [UC]) were evaluated using clinical indexes and followed up to assess for treatment escalation. Sixty-eight patients underwent endoscopic evaluation at baseline. In the second cohort of 46 biologically treated patients, treatment response was assessed. Serum DPP-4, C-reactive protein (CRP), and fecal calprotectin levels were quantified at baseline and during follow-up. Results: Median DPP-4 levels were significantly lower in active IBD patients when compared with remitters (CD: 1043 [831–1412] vs 1589 [1255–1956] ng/mL; P < 0.001; UC: 1317 [1058–1718] vs 1798 [1329–2305] ng/mL; P = 0.001) and healthy controls (2175 [1875–3371] ng/mL). In fact, DPP-4 was able to distinguish clinical and endoscopic activity from remission, with areas under the curve (AUC) of 0.81/0.93 (CD) and 0.71/0.79 (UC), along with the need for treatment escalation, with comparable AUCs of 0.79 (CD) and 0.77 (UC). Furthermore, DPP-4 levels were higher in responders to treatment and more pronounced among UC (1467 [1301–1641] vs 1211 [1011–1448] ng/mL; P < 0.001) than CD patients (1385 [1185–1592] vs 1134 [975–1469] ng/mL; P = 0.015). Conclusions: Our results suggest that serum DPP-4 can be used as a noninvasive biomarker of IBD activity and biological treatment response and a predictor of treatment escalation, particularly when combined with other biomarkers.
Accuracy of the new rapid test for monitoring adalimumab levels
Publication . Rocha, Cátia; Afonso, Joana; Lago, Paula; Arroja, Bruno; Vieira, Ana I.; Dias, Cláudia C.; Magro, Fernando
Background: The loss of response to adalimumab (ADL) has been related to low serum concentrations at trough. Currently, most methods commercially available for the quantification of ADL are enzyme-linked immunosorbent assay (ELISA) based, with a turnaround time of approximately 8 h, delaying the target dosage adjustment to the subsequent infusion. In this study, we aimed to evaluate the performance of the newly available rapid-test ADL quantification assay by comparing it with three established ELISA methods, using spiked samples and a set of clinical samples. Methods: Spiked samples from control donors and 120 serum samples from inflammatory bowel disease (IBD) patients undergoing ADL therapy were quantified using lateral flow Quantum Blue® Adalimumab and, the ELISA formats from Immundiagnostik, R-Biopharm and an in-house assay. Results: The rapid-test assay had intraclass correlation coefficients of 0.590, 0.864 and 0.761 when comparing with the Immundiagnostik, R-Biopharm and in-house assays, respectively. For the five therapeutic windows, the accuracy was high: ADL rapid test compared with the Immundiagnostik (58–88%); R-Biopharm, 68–89%; and in house, 60–88%; and kappa statistics revealed 0.492–0.602, 0.531–0.659 and 0.545–0.682, respectively. Conclusions: The Quantum Blue® Adalimumab assay can replace the commonly used ELISAbased ADL quantification kits and it is a reliable alternative to these methods. This rapidtest assay enables the quantitative determination of ADL serum trough level in only 15 min. The developed assay allows measurement of ADL over a wide range. Hence, it represents a valuable tool for the clinician to assess the ADL trough level.
Evolution and precision of point-of-cares in therapeutic drug monitoring in IBD
Publication . Rocha, Cátia Sofia Lourenço; Magro, Fernando; Diógenes, Maria José; Machado, Patrícia
The advance of knowledge about the pathogenesis of inflammatory bowel disease (IBD) has allowed for the discovery of potential treatments aimed at biological targets. Thus, in the early 90’s, IBD treatment entered a new era, with the development of biological therapies. However, some patients do not respond to induction treatment (primary loss of response) or lose response during maintenance treatment (secondary loss of response) over time. This loss of response may be related to these treatments being highly immunogenic, thus leading to the development of anti-drug antibodies (ADAs), which can neutralize drug-target binding or increase drug clearance, resulting in sub-optimal drug concentrations and shorter response times. Usually, this loss of response is managed empirically. However, this empirical approach increases the risk of irreversible tissue damage and health care costs, and may delay effective IBD treatment. Therefore, therapeutic drug monitoring (TDM) is an emerging strategy in the treatment of IBD patients. Assessing both drug and ADAs levels can help clinicians adjust therapy on individual basis. However, its proper use depends on knowledge of the pharmacokinetic properties that influence loss of response and on the correct use of methods for detecting drug and ADA levels. The global aim of this work was to understand the impact of the methodological approach of TDM and the consequent biases in its interpretation in IBD patients treated with anti-TNFα drugs. This work demonstrated that the presence of the drug influences the detection of ADAs and this impact is methodology-dependent. Therefore, the inability of some assays to determine ADAs in the presence of the drug may hamper the clinical interpretation of TDM. Moreover, this work also demonstrated that the methodologies used for TDM of Remicade® can also be used to monitor the levels of Flixabi® (Remicade-biosimilar). In addition, we also demonstrated that Remicade®, Remsima® and Flixabi® show a high cross-immunogenicity, which supports their high similarity, but prevents their exchange, as an efficacious therapeutic option, in patients who do not respond to anti-TNFα therapy.
This work shows that TDM can be advantageous in: i) identifying medication adherence problems in patients who have lost response, allowing clinicians to discriminate between pharmacokinetic and pharmacodynamic reasons for treatment failure; ii) identification of the most appropriate dosing regimen to achieve the optimal response with minimal toxicity; iii) help clinicians identify patients who will and will not benefit from treatment. However, the use of TDM should always be integrated with the identification of possible methodological biases and the clinical assessment of the patient.
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Fundação para a Ciência e a Tecnologia
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PDE/BDE/114583/2016