**6. Future perspectives in the management of systemic vasculitis**

#### **6.1. Inhibitors of B cell maturation**

BAFF (B lymphocyte survival Factor, BLyS) is a member of the tumor necrosis factor (TNF) family and is expressed on the surface of monocytes, dendritic cells (DC), neutrophils, stromal cells, activated T cells, malignant B cells and epithelial cells. BAFF binds to three different receptors, BAFF-R, TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), that are expressed differentially at various times during B cell maturation. BAFF enhances long-term B cell survival primarily by up-regulating anti-apoptotic proteins provoking a prompt response

**Figure 10.** B cells maturation and antibody production in autoimmune diseases.

randomized to receive rituximab therapy. Adverse events were not lower in the rituximab

Abbrevaitions: Antineutrophil cytoplasmic autoantibodies; RAVE: Rituximab for ANCA-associated vasculitis; RITUXVAS:

Rituximab may be an effective alternative treatment in newly diagnosed as well as refractory ANCA-associated vasculitis. Wegener's Granulomatosis (granulomatosis with polyangiitis) patients with retro-orbital granulomas tend to be less responsive to rituximab therapy. [91] The great limitation of rituximab is some cases with GPA or microscopic polyangiitis may need to be retreated following initial treatment. New anti-CD20 agents, or agents that attack different B-cell precursors, may overcome this hurdle, and may enable even longer periods of

BAFF (B lymphocyte survival Factor, BLyS) is a member of the tumor necrosis factor (TNF) family and is expressed on the surface of monocytes, dendritic cells (DC), neutrophils, stromal cells, activated T cells, malignant B cells and epithelial cells. BAFF binds to three different receptors, BAFF-R, TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), that are expressed differentially at various times during B cell maturation. BAFF enhances long-term B cell survival primarily by up-regulating anti-apoptotic proteins provoking a prompt response

**6. Future perspectives in the management of systemic vasculitis**

Rituximab versus cyclophosphamide in ANCA-associated vasculitis. [55,56]

**Table 2.** Demographics of patients enrolled in RAVE and RITUXVAS.

remission.

**6.1. Inhibitors of B cell maturation**

group as had been expected. [90]

256 Updates in the Diagnosis and Treatment of Vasculitis

of B cells to BCR activation. TACI and BCMA signal through the classic NF-κB pathway and through the Mek (mitogen-activated protein extracellular signal-related kinase) pathway to up-regulate anti-apoptotic and down-regulate pro-apoptotic pathways, and through JNK/p38 (c-Jun N-terminal kinase) to drive class-switching. Survival and reactiva‐ tion of B cell memory is BAFF-independent. Plasma cells express TACI and/or BCMA and their survival can be supported by either BAFF or APRIL. In contrast, B1 cells do not require BAFF or APRIL for survival. BAFF plays an important role in humoral immuni‐ ty. T cell-independent type II responses require the interaction of BAFF 60-mer or membrane BAFF with TAC. This interaction is vital for T cell-dependent immunoglobu‐ lin (Ig)M responses. BAFF is also an essential component of the innate immune response and is induced in myeloid DC by type I interferons (IFNs). BAFF up-regulates Toll-like receptor (TLR) expression, promotes B cell survival and, together with IL-6, promotes Ig class-switching and plasma cell differentiation. Soluble BAFF and APRIL are expressed at high levels in the serum and in the target organs of individuals with established anti‐ body dependent autoimmune diseases. Therapeutic antagonism of BAFF and its homo‐ logue APRIL (a proliferation-inducing ligand) targets an important homeostatic signal for B cell survival and selection (Figure 10). Belimumab and atacicept are two potential therapeutic anatgonists to the BAFF-APRIL pathway for B cell activation that are current‐ ly being investigated. [92-105]

#### *6.1.1. Belimumab*

Belimumab (LymphoStat-B; Human Genome Sciences, Inc., Rockville, MA, USA) is a recombi‐ nant, fully human IgG1λ monoclonal B-lymphocyte stimulator inhibitor that binds to soluble BLyS with high affinity. The drug exerts its biologic activity by preventing the binding of BLyS to its receptors. Belimumab potently inhibits BLyS-induced proliferation of B cells *in vivo and vitro* and prevents human BLyS-induced increases in splenic B-cell numbers and serum IgA titers. Belimumab is the only biologic approved for the treatment of systemic lupus erythe‐ matosus. Experimental evidences support the possible benefit in other B cell dependent autoimmune diseases including vasculitis. [106]

#### *6.1.2. Atacicept*

Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. Experimental studies demonstrated the efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. [107] The use of atacicept as an alternative B cells targeted therapy in refractory vasculitis remains to be investigated.

thereby preventing the signalling associated with IL-6 binding to its receptor. Tocilizumab is currently being investigated as a possible remission induction alternative in old aged patients withactiveGiant cellarteritiswhoare intolerable tohighdosesof steroidandasasteroidsparing agent that might provide substantial long term benefit for these patients. [110, 111] Figure 12

**Figure 11.** T cells targeted biologic therapy. T cells require two signals to become fully activated. A first signal which is antigen-specific is provided through the T cell receptor which interacts with peptide MHC molecules on the mem‐ brane of the antigen presenting cells (APC). A second signal, the co-stimulatory signal, is antigen non-specific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell. One of the best characterized co-stimulatory molecules expressed by the T cells is CD-28, which interacts with CD80 (B7.1) and CD86 (B7.2) on the membrane of APC. MHC: major histocompatibility complex, APC: antigen presenting

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**Figure 12.** The role of interleukin-6 in autoimmunity.

cells.

#### **6.2. Inhibition of T cell co-stimulation**

T cells require at least two signals for activation. The first is an antigen driven signal delivered when the antigen binds to the T-cell receptor. The second is a co-stimulatory signal delivered by receptor ligand interactions between the T cell and the antigen-presenting cell (eg, CD28 and B7.1). Binding of CD28 to B7.1 upregulates the production of multiple cytokines by CD8+ and CD4+ cells especially interleukin2 (IL-2) and interferon-gamma. The potential role of this approach is just beginning to be explored for patients with systemic vasculitis. (Figure 11)

#### *6.2.1. Abatacept*

Soluble, recombinant, fully-human fusion protein, comprising the extracellular domain of CTLA-4 linked to the Fc (hinge, CH2 and CH3 domains) portion of immunoglobulin G1. Abatacept is an inhibitor of T-cell co- stimulation, is being explored as a potential treatment for GPA, TAK, and GCA. [108, 109]

#### **6.3. Other potential suppressors of T cells effector functions [Anti-cytokine therapy]**

#### *6.3.1. Tocilizumab*

The first humanized monoclonal antibody that targets and inhibits the human interleukin-6. Tocilizumab binds both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R),

**Figure 11.** T cells targeted biologic therapy. T cells require two signals to become fully activated. A first signal which is antigen-specific is provided through the T cell receptor which interacts with peptide MHC molecules on the mem‐ brane of the antigen presenting cells (APC). A second signal, the co-stimulatory signal, is antigen non-specific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell. One of the best characterized co-stimulatory molecules expressed by the T cells is CD-28, which interacts with CD80 (B7.1) and CD86 (B7.2) on the membrane of APC. MHC: major histocompatibility complex, APC: antigen presenting cells.

thereby preventing the signalling associated with IL-6 binding to its receptor. Tocilizumab is currently being investigated as a possible remission induction alternative in old aged patients withactiveGiant cellarteritiswhoare intolerable tohighdosesof steroidandasasteroidsparing agent that might provide substantial long term benefit for these patients. [110, 111] Figure 12

**Figure 12.** The role of interleukin-6 in autoimmunity.

*6.1.1. Belimumab*

258 Updates in the Diagnosis and Treatment of Vasculitis

*6.1.2. Atacicept*

*6.2.1. Abatacept*

*6.3.1. Tocilizumab*

autoimmune diseases including vasculitis. [106]

vasculitis remains to be investigated.

**6.2. Inhibition of T cell co-stimulation**

for GPA, TAK, and GCA. [108, 109]

Belimumab (LymphoStat-B; Human Genome Sciences, Inc., Rockville, MA, USA) is a recombi‐ nant, fully human IgG1λ monoclonal B-lymphocyte stimulator inhibitor that binds to soluble BLyS with high affinity. The drug exerts its biologic activity by preventing the binding of BLyS to its receptors. Belimumab potently inhibits BLyS-induced proliferation of B cells *in vivo and vitro* and prevents human BLyS-induced increases in splenic B-cell numbers and serum IgA titers. Belimumab is the only biologic approved for the treatment of systemic lupus erythe‐ matosus. Experimental evidences support the possible benefit in other B cell dependent

Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. Experimental studies demonstrated the efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. [107] The use of atacicept as an alternative B cells targeted therapy in refractory

T cells require at least two signals for activation. The first is an antigen driven signal delivered when the antigen binds to the T-cell receptor. The second is a co-stimulatory signal delivered by receptor ligand interactions between the T cell and the antigen-presenting cell (eg, CD28 and B7.1). Binding of CD28 to B7.1 upregulates the production of multiple cytokines by CD8+ and CD4+ cells especially interleukin2 (IL-2) and interferon-gamma. The potential role of this approach is just beginning to be explored for patients with systemic vasculitis. (Figure 11)

Soluble, recombinant, fully-human fusion protein, comprising the extracellular domain of CTLA-4 linked to the Fc (hinge, CH2 and CH3 domains) portion of immunoglobulin G1. Abatacept is an inhibitor of T-cell co- stimulation, is being explored as a potential treatment

**6.3. Other potential suppressors of T cells effector functions [Anti-cytokine therapy]**

The first humanized monoclonal antibody that targets and inhibits the human interleukin-6. Tocilizumab binds both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R),

#### *6.3.2. Dacilizumab*

A humanized IgG1 monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human highaffinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes. Dacilizumab proved to be an effective alternative in interferon refractory relapsing remitting multiple sclerosis. The drug is currently being investigated in autoimmune diseases including ANCA associated vasculitis. [112]

**7. Secondary vasculitis**

tenance of remission. [115]

**AASV**

The role of biologic therapy in the management of leukocytoclastic vasculitis secondary to rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome has not been fully explored. Anti-tumor necrosis factor (TNF) treatment proved to be effective in rheumatoid arthritis patients with refractory systemic rheumatoid vasculitis after failure of conventional therapy including cyclophosphamide and corticosteroids with successful tapering of cortico‐ steroids. The use of anti-TNF therapy and other biologic drugs might be considered in refractory secondary vasculitis to induce remission and as steroid sparing therapy for main‐

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**8. Special considerations in ANCA Associated Small vessels Vasculitis**

Therapeutic targets that are currently being considered in ANCA associated vasculitis include: (a) Inhibition of adhesion and activation of neutrophils aiming to dampen vascular injury. (b) Boosting vascular repair via endothelial progenitor cells (EPCs) which are regarded as an important factor of vascular repair. EPC mobilization and function might be enhanced by additional treatment with erythropoietin (EPO) or statins. (c) The use of antibiotics (cotrimox‐

The development of recombinant technology represented the single biggest advance leading to humanized products with minimal or no contaminants in comparison to products purified from animal tissues. Nevertheless, the type of manufacturing process including choice of cell type, culture medium, and purification method can result in changes to the protein. Mono‐ clonal antibodies represent a major class of successful biologics. Toxicities associated with these agents include those associated with the binding of the complementary determining region (CDR) with the target biologic molecule. [117, 118] Most of the concerns about safety of biologic therapy are related to the use of biologic agents particularly TNFi in the treatment

Bacterial, mycobacterial and fungal infections might occur during biologic therapy especially with tumor necrosis factor inhibitors. Infections usually occur in first year of treatment, including life threatening serious infections and mostly caused by intracellular pathogens (tubercle bacillus, listeria, histoplasma, atypical mycobacteria, coccidioidomycosis and legionella). Infection risk with biologic therapy in patients with autoimmune diseases signif‐

icantly correlated to the dose of glucocorticoids given in such patients.

azole) might prevent disease flares triggered by bacteria.

**9. Hazards of biologic therapy**

of rheumatoid arthritis.

**9.1. Infections**

#### *6.3.3. Basiliximab*

A chimeric (murine/human) monoclonal antibody (IgG1K), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin-2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes, inhibiting the binding of IL-2 to it's receptor on target T cells. The drug is being currently used for treatment of allograft rejection and potentially under consideration for the ANCA associated vasculitis. [113, 114]


**Table 3.** Current and future considerations in treat to target strategy in systemic vasculitis.[116]
