1.
Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis.
Paul, S, Marotte, H, Kavanaugh, A, Goupille, P, Kvien, TK, de Longueville, M, Mulleman, D, Sandborn, WJ, Vande Casteele, N
Clinical and translational science. 2020;(4):743-751
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Abstract
Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 μg/ml at week 12, and ≥ 17.6 μg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.
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Use of (1→3)-β-d-glucan for diagnosis and management of invasive mycoses in HIV-infected patients.
Farhour, Z, Mehraj, V, Chen, J, Ramendra, R, Lu, H, Routy, JP
Mycoses. 2018;(10):718-722
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Abstract
People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-d-glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.
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Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.
Ryan, JD, Altamura, S, Devitt, E, Mullins, S, Lawless, MW, Muckenthaler, MU, Crowe, J
Hepatology (Baltimore, Md.). 2012;(2):492-500
Abstract
UNLABELLED Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.
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Flow cytometry-based pharmacodynamic monitoring after organ transplantation.
Dieterlen, MT, Eberhardt, K, Tarnok, A, Bittner, HB, Barten, MJ
Methods in cell biology. 2011;:267-84
Abstract
Conventional therapeutic drug monitoring based on measuring immunosupressive drug concentrations in blood is important in the clinical management of immunosuppressive therapy in transplantation medicine. Since rejection or infection occurs at irregular drug concentrations immunosuppressive drug therapy is often empiric and prophylactic in nature. In addition, blood immunosuppressant levels are only indirect predictors of the pharmacologic effects on immune cells, because the genetic heterogeneity the immune systems of transplant recipients are not equally sensitive to drug effects. Therefore, therapeutic drug monitoring requires the application of reliable and effective methods to study the pharmacodynamic variability by direct measurements of drug effects on immune cell functions. Flow cytometry offers a multiplicity of quantitative analysis possibilities, from detection of phosphorylated molecules up to complex multicolor analysis of whole blood samples. A large spectrum of flow cytometry-based applications for pharmacodynamic monitoring is available and allows detection and analysis of diverse function of T cells and dendritic cell subsets. By combining several assays, it is possible to generate a broad picture of the immune status of every single transplanted recipient. Furthermore, it is even possible to differentiate between synergistic and antagonistic pharmacodynamic effects of immunosuppressive drug combination therapy in vitro and to predict the pharmacodynamic drug effects in transplanted recipients. Such a pharmacodynamic drug monitoring may offer the opportunity to complete conventional therapeutic drug monitoring and, therefore, to tailor immunosuppressive therapy more individually.