Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels*

Panacek, Edward A.; Marshall, John C.; Albertson, Timothy E; Johnson, David H.; Johnson, Steven B.; MacArthur, Rodger D.; Miller, Mark J.S.; Barchuk, William; Fischkoff, Steven A.; Kaul, Martin; Teoh, Leah; Meter, Lori Van; Daum, Lothar; Lemeshow, Stanley; Hicklin, Gregory A.; Doig, Christopher J.

doi:10.1097/01.ccm.0000145229.59014.6c

Cited by 345 publications

(199 citation statements)

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“…A 2004 trial examining anti-tumor necrosis factor therapy in patients with severe sepsis with elevated levels of IL-6 is a classic failed example. Although IL-6 was a strong prognostic marker (higher mortality in patients in the placebo arm with elevated IL-6), it did not predict treatment response (similar RRR between IL-6-positive and IL-6-negative patients) in the primary unadjusted analysis (50).…”

Section: Incorporating Of Biomarkers For Therapy Responsiveness Into mentioning

confidence: 79%

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Prescott

Calfee

Thompson

et al. 2016

Am J Respir Crit Care Med

272

237

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Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

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Section: Incorporating Of Biomarkers For Therapy Responsiveness Into mentioning

confidence: 79%

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Prescott

Calfee

Thompson

et al. 2016

Am J Respir Crit Care Med

272

237

View full text Add to dashboard Cite

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“…Treatment with Afelimomab, an anti-TNF-α antibody in patients of severe sepsis showed significant attenuation in IL-6, TNF-α levels and severity of organ dysfunction [32]. Treatment with etanercept, a TNF-α antagonist, for twelve weeks in patients of refractory asthma showed significant improvement in asthma control and systemic inflammation [33].…”

Section: Cytokines As Therapeutic Targetsmentioning

confidence: 99%

“…Disease Targets IFN-α Hepatitis B and C [5] IFN-β Multiple sclerosis [5] IFN-γ Chronic granulomatous disease [38], Crohn's disease [65], Multidrug resistant tuberculosis [42] TNF-α Rheumatoid arthritis [30,31], Sepsis [32], Refractory asthma [33], Psoriasis [2] G-CSF Idiopathic neutropenia, Congenital neutropenia, Febrile neutropenia, Leukemic neutropenia, Aplastic neutropenia [37], Bone marrow suppression [5] GM-CSF Bone marrow suppression, Crohn's disease [5] IL-2 Metastatic melanoma, Renal cell carcinoma [46] IL-4 Asthma [43] IL-5 Asthma [44] IL-6 Rheumatic diseases [34] IL-10 Crohn's disease, Ulcerative colitis [2], Psoriasis, Rheumatoid arthritis [5] IL-11 Crohn's disease, Ulcerative colitis, Psoriasis, Rheumatoid arthritis [2] IL-13 Asthma [2,45] Erythropoietin Anaemia, Bone marrow failure [5] HER2-Specific Monoclonal Antibody Adenocarcinoma of stomach, Breast cancer [35,36] …”

Section: Cytokinesmentioning

confidence: 99%

“…Because cytokines are potential rate-limiting molecules in various diseases, therefore, they are the excellent targets for the biotechnology products like monoclonal antibodies and antibody-like receptor: Fc fusion proteins for the pharmaceutical industry [29]. One of the very initial applications showed that treatment with TNF-α blocker suppressed disease activity and attenuated joint deformation and destruction in rheumatoid arthritis-highlighting the importance of cytokine antagonists in disease [30,31].Treatment with Afelimomab, an anti-TNF-α antibody in patients of severe sepsis showed significant attenuation in IL-6, TNF-α levels and severity of organ dysfunction [32]. Treatment with etanercept, a TNF-α antagonist, for twelve weeks in patients of refractory asthma showed significant improvement in asthma control and systemic inflammation [33].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cytokines and their Role in Health and Disease: A Brief Overview

Gulati¹,

Guhathakurta²,

Joshi³

et al. 2016

MOJI

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Cytokines are small, non-structural proteins with low molecular weights which have a complex regulatory influence on inflammation and immunity. It has long been considered that development of immune and inflammatory response involves hematopoietic cells, lymphoid cell, and various pro-inflammatory and anti-inflammatory cells, and cytokines mediate the complex interactions of these cells. Cytokines are the intercellular messengers in the immune system where they integrate function of several cell types in various body compartments into a coherent immune response. They have evolved over the years and now include the interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. Earlier known as `soluble factors`, cytokines are produced by and elicit a response from every cell, with the lone exception of the red blood cell. In response to various stimulus cytokines are secreted from various cells including white blood cells. Pleiotropism is the hallmark of a cytokine and there are failures and successes of cytokines and related agents as therapeutic agents. In the membrane of target cells they have specific receptors for their signal transduction and regulatory functions. Beyond the innate and adaptive immunity, cytokines has a major role in many diverse functions including immune cell differentiation, inflammation, angiogenesis, tumorigenesis, neurobiology, viral pathogenesis etc. In addition to inflammation, immunity and infections, cytokines have now expanded their domain to atherosclerosis and cancer. Thus, cytokines may be useful biomarkers for health and disease and act as diagnostic, prognostic and therapeutic agents. This review will highlight the impact of cytokines in various physiological actions, pathophysiological states, therapeutics and the complex interactions between brain and immune cells. knowledge has highlighted the complexity and biphasic nature of cytokines -and the same molecule may have beneficial as well as detrimental effects. For example, interferon-γ (IFNγ), which is essential for defense against several intracellular microorganism such as Mycobacterium tuberculosis, is also a major cytokine in the pathogenesis of several autoimmune diseases. IL-2 is needed for the generation of cytotoxic T-cells (CTL) and forms the basis for several vaccines but the same cytokine drives graft versus host disease and limits the success of bone marrow transplantation [5]. Keywords: Cytokine ReceptorsThe cytokines exert various biological effects through receptors present on the membranes of responsive target cells. These receptors have an extracellular domain, a cytoplasmic domain and a single membrane spanning domain. There is the presence of conserved amino acid sequence motifs on the extracellular domain and these motifs include four conserved cysteine residues. There is also the presence of two polypeptide chains. One is the cytokine specific α subunit and other is a signal transducing β subunit.The nature of the target cell ...

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“…In the 1980s and 1990s, multiple therapies targeting proinflammatory mediators and aimed at reducing inflammation reached phase III clinical trials in adults with severe sepsis and septic shock [1][2][3][4][5][6][7][8][9][10][11][12]. Nearly all of these studies failed to demonstrate a survival benefit, suggesting that perhaps reducing inflammation is not the appropriate therapeutic goal in all cases.…”

Section: Introductionmentioning

confidence: 99%