The pathogenesis of rheumatoid arthritis. Systemic treatment: immunotherapy. Oxford Medicine Online

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Oxford Medicine Online

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The pathogenesis of rheumatoid arthritis

Catherine Swales, and Paul Wordsworth Raashid Luqmani (ed.)

Print Publication Year: 2010 Published Online: May 2011 ISBN: 9780199556755 eISBN: 9780199607334

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199556755.003.0002

• Many cell types and mediators are implicated in the pathogenesis of rheumatoid arthritis • Tumour necrosis factor alpha (TNF#) is currently identified as one the most important cytokines responsible for mediating inflammation and damage in arthritis • Interleukin-17 (IL-17) has been found to regulate many cytokines including TNF# • T helper 17 (TH17) and T helper 1 (TH1) cells are the dominant T cell subsets in rheumatoid synovium • Novel mechanisms for perpetuation of arthritis are being elucidated, which may lead to more effective therapeutic strategies in future.

Systemic treatment: immunotherapy

Bernard Escudier, Marine Gross Goupil, Christophe Massard, and Karim Fizazi

Print Publication Year: 2010 Published Online: Sep 2011 ISBN: 9780199562312 eISBN: 9780199607402

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199562312.003.0006

• For 20 years, immunotherapy has been the standard of care for renal cell carcinoma (RCC) • Although the new targeted therapies have dramatically changed the landscape of this disease, immunotherapy remains an attractive therapeutic option in this disease • Initially, there have been two main reasons for developing immunotherapy in RCC • The resistance to any kind of chemotherapy • The observation that spontaneous remission was observed in this disease, strongly suggesting the role of immune system • The enthusiasm for immunotherapy was then greatly stimulated by the initial results of high-dose interleukin 2 (IL-2), demonstrating a significant proportion of patients achieving partial or even

complete remission, with sustained responses and long-lasting responses. Furthermore, the first results with the use of interferon (IFN) confirmed that responses could be observed with cytokines • These exciting data stimulated research in the field of immunology and immunotherapy of RCC, and led to the attempt to treat the disease with different types of immune manipulations, including cell therapy, vaccines, and bone marrow transplantation.

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Assessment of treatment options in renal cancer

Martin Gore and Sheeba Irshad

Print Publication Year: 2010 Published Online: Sep 2011 ISBN: 9780199562312 eISBN: 9780199607402

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199562312.003.0003

• Several models have been developed as prognostic tools to select patients for treatment strategies, analyse results of clinical trials, and give information to patients regarding prognosis • For localized and locally advanced tumours, surgery is the gold standard • Observation remains standard of care after nephrectomy but results of current adjuvant phase III trials are awaited • Published phase III trials have established the novel targeted agents as standard of care for patients with metastatic renal cell carcinoma (mRCC) • Only selected patients with mRCC, revealing a good-risk profile, and clear cell subtype histology have any chance of deriving clinical benefit from immunotherapy.

Neurobiology of cognitive dysfunction in major depressive disorder

Roger S. McIntyre, Danielle S. Cha, and Joanna K. Soczynska

Print Publication Year: 2014 Published Online: Jul 2014 ISBN: 9780199688807 eISBN: 9780191767982 Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199688807.003.0007

• Cognitive deficits in MDD are subserved by disturbances in several integrated neural, neurotransmitter, inflammatory, oxidative, endocrine systems. • In general, the effects of disparate neurobiological systems on cognitive function follow an inverted U shape pattern, suggesting that absence and excess are detrimental to cognition and superior cognitive performance likely occurs at an optimal level of function.

Aetiopathogenesis of systemic lupus erythematosus

Peter Lloyd, Sarah Doaty, and Bevra H. Hahn

Print Publication Year: 2016 Published Online: May 2016 ISBN: 9780198739180 eISBN: 9780191802287

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780198739180.003.0002

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of immune dysregulation, autoreactive B and T cells, and the production of a broad, heterogeneous group of autoantibodies (autoAb). The pathogenesis of lupus can be divided into three stages: 1) genetic predisposition and environmental exposures, 2) loss of tolerance, and 3) immune activation. In this chapter we will discuss the aetiopathogenesis of systemic lupus erythematosus with emphasis placed on key autoantibodies, cytokines, the innate and adaptive immune system, tolerance, NETosis, genetics and epigenetics, environmental triggers and the role of gender.

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Pathology and molecular features of COPD

Andrew J. Tan

Trevor T. Hansel (ed.) , and Onn Min Kon (ed.)

Print Publication Year: 2008 Published Online: May 2011 ISBN: 9780199549146 eISBN: 9780199607273

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199549146.003.0002

• Cigarette smoke is estimated to contain 1017 reactive oxidant species (ROS) and chronic smoking in genetically susceptible individuals is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). • COPD involves a spectrum of diseases: chronic bronchitis, obstructive bronchiolitis, emphysema, pulmonary vascular disease, cor pulmonale, and a systemic syndrome of cachexia and muscle weakness. • ROS trigger an exaggerated host inflammatory, mucosecretory, proteolytic, and fibrotic response. Epithelial cell injury and macrophage activation causes release of chemotactic factors and cytokines such as CXCL1, CXCL8, CCL2, and TNF-#. • Macrophages and neutrophils then release proteases, with involvement of matrix metalloproteases (MMPs) and neutrophil elastase (NE) that may break down extracellular matrix (ECM). T cells of various subtypes (Th1, Th2, Tc1, Tc2, Treg, Th17) as well as B cells may also be involved in this inflammatory cascade. • Transforming growth factor-#1 (TGF-#1) is produced by epithelial cells and causes fibrosis. Inhibition of fibrosis is caused by interferon-# (IFN-#), while profibrotic factors include interleukin-13 (IL-13), platelet-derived growth factor (PDGF), CCL2 (MCP-1) and CXCL12 (ligand for CXCR4), and protease activated receptor 2 (PAR-2). • Many years of injury from cigarette smoke causes cycles of inflammation and repair. These cycles may result in resolution, but are commonly associated with mucus hypersecretion, fibrosis, proteolysis, and both airway and parenchymal remodelling.

Clinical physiology of testosterone

T. Hugh Jones

Print Publication Year: 2012 Published Online: Dec 2012 ISBN: 9780199651672 eISBN: 9780191742958

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199651672.003.0002

Adequate tissue androgenization is dependent on a balance of testosterone synthesis and breakdown, the fraction of biologically active testosterone in the circulation and

available to the tissues, androgen receptor sensitivity, and non-genomic effects. Circulating testosterone is divided into three major fractions: free, albumin-bound, and SHBG-bound. The free plus the albumin-bound testosterone constitutes the bioavailable testosterone. The CAG androgen receptor polymorphism affects sensitivity of the receptor and has clinical consequences. Testosterone has actions independent of the classical androgen receptor, which mediate effects through non-genomic mechanisms. Testosterone levels are affected adversely by age and obesity.

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Future treatments in rheumatoid arthritis

Raashid Luqmani and Paul P Tak

Print Publication Year: 2010 Published Online: May 2011 ISBN: 9780199556755 eISBN: 9780199607334

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199556755.003.0012

• New treatments are required for the management of rheumatoid arthritis • A greater understanding of disease mechanisms should allow the development of a more rational approach to therapy • New strategies include combination biologic therapy, targeting of synovial fibroblasts, personalized therapy based on disease profiles, local gene therapy, and vaccination.

Biologic therapy

Peter Taylor

Print Publication Year: 2010 Published Online: May 2011 ISBN: 9780199556755 eISBN: 9780199607334

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780199556755.003.0006

• Biologic therapies for RA are protein-based drugs which target specific components of the immune system known to be of pathogenic relevance • Biologic therapeutics targeting tumor neurosis factor alpha (TNF#) have been successful in suppressing inflammation and markedly inhibiting the progression of structural damage; five anti-TNF agents are now available: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab • Biological TNF# inhibitors have greatest efficacy for improvement in symptoms and signs and prevention of structural damage when used in combination with methotrexate • Rituximab is a biologic agent that depletes B cells for use after failure of an anti-TNF biologic agent • Abatacept, which targets the co-stimulatory pathway of inflammation, is approved for use in many countries (but not in the UK) • Other biologic therapies directed against different immune targets have been licensed for use in RA or are in development but have not yet been approved by NICE • Several new, non-biologic agent approaches to immuno-modulatory therapy for RA are also in development.

Aetiology and pathogenesis

Georgina Espígol-Frigolé, Ester Planas-Rigol, Marc Corbera-Bellalta, Nekane Terrades-García, Marco A. Alba, Sergio Prieto-González, José Hernández-Rodríguez, Bhaskar Dasgupta, and Maria C. Cid

Print Publication Year: 2016 Published Online: May 2016 ISBN: 9780198729204 eISBN: 9780191795909

Item type: chapter

Publisher: Oxford University Press

DOI: 10.1093/med/9780198729204.003.0002

Genetic background plays a significant role in the pathogenesis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Both T-helper (Th)1 and Th17-mediated immune

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synovial inflammation in PMR are less understood. Vascular remodelling in response to inflammation leads to vascular occlusion and ischaemic complications in GCA.

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