**1. Introduction**

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Systemic necrotizing vasculitides are a broad family of conditions characterized by injury or destruction of the blood vessel walls by inflammatory cells with subsequent vessel occlusion and ischemic tissue injury with high rates of morbidity and mortality. [1] The heterogeneous nature of the involved etio-pathogenetic mechanisms together with the diversities in clinical presentations poses a great challenge to successful induction and maintenance therapy in vasculitis.Untreated,thesediseasescanbedevastating.Treatmentstrategyinvasculitisdepends entirely upon the type of vasculitis, the pattern and severity of organ involvement. High dose corticosteroids and cytotoxic drugs remain the cornerstones in the management of vasculitis that dramatically improved the prognosis with increasing chances for remission. However, despite suchaggressive therapythe relapse rate insystemicvasculitis ranges from30-50%.With theincreasingrelapses insomecases,refractoriness tostandardcaremeasures inothers together with the toxicities associated with the use of long term high dose corticosteroids and cytotoxic drugs there is an increasing demand for an alternative effective therapy.

Thepathogeneticbackgroundinhumanautoimmunediseases remainspoorlyunderstood.The recent advances in the understanding of epigenetics of autoimmune rheumatic diseases have revealed a variety of disease specific pathways responsible for immune-mediated inflammato‐ ry and destructive events. In most of these situations including vasculitis the initial trigger is mostly an infectious trigger. It is mostly an antigen driven response that involves activation of the antigenpresentingcells (dendritic cells,macrophages,monocytes,Blymphocytes),priming of T lymphocytes towards a Th1, Th17 response. The primed Th1, Th17 lymphocytes initiates a cascade of pro-inflammatory events involving the release of pro-inflammatory cytokines (TNF alpha, IL-1 β,IL-6, TGF- β, IFN-γ, IL-17, IL-23) with subsequent priming of neutrophils, overexpression of adhesion molecules, activation of co-stimulatory signals with further release of pro-inflammatory mediators and autoantibody production. Figure 1

© 2013 Mohammed; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Figure 1.** Basic pathogenic theory of autoimmunity in vasculitis.

Advances in the understanding of the pathogenesis of autoimmune diseases, allow increasing‐ ly specific, targeted therapies to be developed for clinical use. These therapies are nominated as biologic disease modifying drugs that fall under two categories: anti-cytokine strategies, and drugs thattarget specific subsetsofimmune cells.Theultimategoalofthese therapies is totarget pathogeneticpathwaysthatcontributetodiseaseinitiationandprogression.Therecentattempts to use biologic disease modifying drugs in refractory systemic vasculitis has revolutionized the therapeutic landscape with promising observable outcome. [2]

## **2. Tumor necrosis factor alpha in vasculitis**

TNF-α, with its' brother lymphotoxin TNF-β, represent a family of pro-inflammatory cyto‐ kines produced by a variety of immune cells, primarily by lipopolysaccharide-stimulated macrophages and monocytes, as well as by T lymphocytes. TNF exists in both cell membranebound and soluble forms with TNF receptors (TNF- R1, TNF- R2) on many cells, including macrophages and monocytes, thereby allowing it to stimulate its own production and release. It has been shown to be a key cytokine in the host inflammatory response. Its actions are modulated through various mechanisms, which include adhesion molecule expression, proinflammatory cytokine release, synthesis of chemokines, inhibition of regulatory T cells and activation of a variety of immune cells. [3, 4]

**Figure 3.** Role of Tumor Necrosis Factor in Inflammatory Response.

**Figure 2.** The Role of Tumor necrosis Factor Targeted Biologic Therapy in Primary Systemic Vasculitides.

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**Antibody mediated cellular cytotoxicity**

**Antigen driven response (Infection)**

**Cytokines – cytokine receptors Vascular Adhesion Molecules Vascular endothelial growth factors** 

> **Vascular Injury Tissue Damage**

Advances in the understanding of the pathogenesis of autoimmune diseases, allow increasing‐ ly specific, targeted therapies to be developed for clinical use. These therapies are nominated as biologic disease modifying drugs that fall under two categories: anti-cytokine strategies, and drugs thattarget specific subsetsofimmune cells.Theultimategoalofthese therapies is totarget pathogeneticpathwaysthatcontributetodiseaseinitiationandprogression.Therecentattempts to use biologic disease modifying drugs in refractory systemic vasculitis has revolutionized the

TNF-α, with its' brother lymphotoxin TNF-β, represent a family of pro-inflammatory cyto‐ kines produced by a variety of immune cells, primarily by lipopolysaccharide-stimulated macrophages and monocytes, as well as by T lymphocytes. TNF exists in both cell membranebound and soluble forms with TNF receptors (TNF- R1, TNF- R2) on many cells, including macrophages and monocytes, thereby allowing it to stimulate its own production and release. It has been shown to be a key cytokine in the host inflammatory response. Its actions are modulated through various mechanisms, which include adhesion molecule expression, proinflammatory cytokine release, synthesis of chemokines, inhibition of regulatory T cells and

**Cell mediated Cytotoxicity**

240 Updates in the Diagnosis and Treatment of Vasculitis

**Figure 1.** Basic pathogenic theory of autoimmunity in vasculitis.

therapeutic landscape with promising observable outcome. [2]

**2. Tumor necrosis factor alpha in vasculitis**

activation of a variety of immune cells. [3, 4]

**Figure 2.** The Role of Tumor necrosis Factor Targeted Biologic Therapy in Primary Systemic Vasculitides.

**Figure 3.** Role of Tumor Necrosis Factor in Inflammatory Response.

The primary immunopathogenic events that initiate the process of vascular inflammation and blood vessel damage remain largely unknown. Granulomatous inflammation involving the vessel itself, the adjacent tissue, or distant sites is a feature of several systemic vasculitic syndromes and tumor necrosis factor is being identified as a major contributor to granulom‐ atous tissue inflammation via its' stimulatory effects on tissue macrophages. The unopposed actions of TNF via its' receptors highly potentiates and sustains inflammatory granuloma formation and integrity. The recognition of the role of this pro-inflammatory cytokine sets it as a potential therapeutic target. Tumor necrosis factor inhibitors have been approved for the treatment of rheumatoid arthritis as well as sero-negative spondylo-arthropathies.

of human TNF-alpha. The drug is given in a dose of 50 mg subcutaneously every 4 weeks. Golimumab is approved for the treatment of rheumatoid arthritis, and seronegative

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Certolizumab: Certolizumab is a PEGylated recombinant, humanized antibody Fab' fragment specific for human tumor necrosis factor alpha (TNFα) that is indicated for treatment of moderately to severely active Rheumatoid Arthritis (RA), treatment and maintenance of remission of moderate to severe active Crohn's disease (CD) in adult patients who have an

The latest two new monoclonal antibody TNF inhibitors, certolizumab and golimumab have been genetically engineered recently aiming to improve affinity and specificity to TNF with better tolerability and less autoimmunity. Neither golimumab nor certolizumab have been

Etanercept: Etanercept: is a dimeric fusion protein composed of two extracellular TNF-receptor domains bound to the Fc portion of human IgG and is injected once or twice weekly at a dose of 50mg. It effectively binds soluble TNF, thereby blocking TNF-receptor activation. [5]

TNF-α is increasingly being implicated in the etio-pathogenesis of several autoimmune diseases, including systemic vasculitis, featuring an interesting therapeutic target. Several case series studies and case reports addressing the role of suppressing tumor necrosis factor in vasculitis have been issued. Such studies have shown that anti TNF therapy might provide a promising therapeutic alternative in the management of refractory systemic vasculitides [8, 9, 10] especially of granulomatous inflammatory nature including; Takayasu's arteritis, probably in giant cell arteritis (GCA) and granulomatous polyangiitis (GPA) amongst other forms of

Takayasu's arteritis is a rare, chronic, systemic panarteritis of unknown etiology characterized by granulomatous inflammation of the aorta and its major branches (occasionally including the pulmonary arteries as well) with progressive fibrosis and stenosis of the affected vessel wall and, less commonly, aneurysm formation. [11, 12, 13] The disease typically presents in women before the age of 40 years old. Glucocorticoids and methotrexate are the mainstays of treatment.[] Amongst the identified pathogenic targets in Takayasu arteritis displayed in (Figure 2), TNF alpha is the only cytokine under evaluation. There have been several case series [14, 15, 16] and case reports [17, 18, 19] that have shown clinical benefit of TNF inhibition for refractory cases with TAK. The use of TNF blockade therapy was associated with significant improvement in BVAS, successful reduction in the dose of oral corticosteroids and longer glucocorticoid drug free remission in cases with refractory Takayasu arteritis. In a case series study by Hoffman et al. including 15 patients with treatment-resistant TAK, patients were

arthropathies. [6]

vasculitis.

inadequate response to conventional therapy. [7]

tried in patients with vasculitis.

*3.4.1. Takayasu vasculitis — TAK*

**3.3. Tumor necrosis factor receptor block**

**3.4. Tumor necrosis factor inhibitors in vasculitis**
