**3. Treatment with biological agents**

#### **3.1 Rituximab**

It is a monoclonal antibody, which is directed against CD20 that is expressed on developing B cell. Although not clearly understood, this antibody can induce apoptosis of these developing B cells. In April 2011, Rituximab was the first agent to be approved by FDA for the treatment of vasculitis [6].

In the Rituximab in ANCA-associated vasculitis (RAVE) trial, patients with GPA and MPA who were being given steroid therapy were randomized and received either oral cyclophosphamide or I/V Rituximab (four infusions). Patients who were given cyclophosphamide were switched to azathioprine after going into remission while those with Rituximab were switched to oral placebo. At the end of 6 months, Rituximab was found to be non-inferior to cyclophosphamide at inducing remission and was found to be superior to cyclophosphamide for patients with relapsing disease [6].

Another study showed single course of Rituximab to be non-inferior to oral cyclophosphamide, which was followed by azathioprine for remission maintenance [7].

In the Rituximab versus cyclophosphamide in ANCA-associated vasculitis (RITUXVAS) trial, where 44 patients were diagnosed with ANCA-associated vasculitis, patients were randomized to receive Rituximab along with only two infusions of cyclophosphamide. This was compared with patients who were given I/V cyclophosphamide for 3–6 months followed by azathioprine. The rate of sustained remission was similar in both groups [8].

These studies indicate that Rituximab is comparable in efficacy to cyclophosphamide for remission induction. Moreover, Maintenance of remission under Rituximab in systemic ANCA-associated vasculitis (MAINRITSAN) trial 115 patients with either GPA or MPA were given either azathioprine or Rituximab in a dose of 500 mg IV × 2 doses (after achieving remission with cyclophosphamide). At the end of the study, major relapse rate was significantly lower in patients who received Rituximab [9].

Rituximab has also shown remarkable results in patients with EGPA whose disease was refractory to usual treatments (e.g. cyclophosphamide). One of the largest case series showed nine patients with EGPA refractory to conventional therapy, when treated with Rituximab were either in total or partial remission at the end of 3 months [10].

The safety and efficacy of Rituximab has been evaluated by Puechal et al. in patients with active systemic rheumatoid vasculitis (SRV). Out of 17 patients with active SRV who were treated with Rituximab, 12 patients achieved complete remission of their disease at the end of 6 months. The Birmingham Vasculitis Activity Score (BVAS) for rheumatoid arthritis dropped down from a baseline of 9.6 to 0.6 and the daily average dose of Prednisolone declined from 19.2 to 9.7 mg. After a year, 14 patients were in sustained remission [11].

Rituximab works by acting over B cells, clearing them from the body. It is the most extensively studied agent that has proved to be efficacious in most forms of vasculitis, especially ANCA-associated vasculitis. It is now the preferred choice over cyclophosphamide in order to reduce the adverse effect profile. Also, Rituximab is considered a suitable therapeutic option for inducing remission in patients with active vasculitis associated with rheumatoid arthritis.

**Table 3** summarizes the clinical outcomes of different trials carried out using Rituximab as treatment for systemic vasculitis.

#### **3.2 Infliximab**

This is an IgG1, kappa monoclonal antibody specific for human tumor necrosis factor alpha. TNF alpha possesses multiple pro inflammatory properties for example, induction of Interleukin 1 and Interleukin 6, neutrophil activation etc. According to recent research, Infliximab is in phase 3 clinical development for treatment of Kawasaki disease [12].

**161**

**Table 4.**

*Infliximab trials [13–15].*

*Treatment of Vasculitis: Beyond the Basics DOI: http://dx.doi.org/10.5772/intechopen.92729*

RITUXVAS trial Rituximab ANCA-

MAINRTSAN trial

*Rituximab trials [6, 8, 9].*

**Table 3.**

One clinical trial studied the role of Infliximab in granulomatosis with polyangiitis exclusively. These patients were followed even after the discontinuation of Infliximab to monitor the remission maintenance. The reduction of their Birmingham Vasculitis Activity Score was significant. Surprisingly no severe

RAVE trial Rituximab GPA and MPA Rituximab was found to be non-inferior to

associated vasculitis

cyclophosphamide at inducing remission and superior to cyclophosphamide for patients with

Rate of sustained remission were similar in patients taking Rituximab vs. those given

relapsing disease

Rituximab GPA/MPA Significantly reduced the relapse rate

cyclophosphamide alone

Use of TNF alpha inhibitors is not encouraged in giant cell arteritis. In a randomized controlled trial, some newly diagnosed patients with giant cell arteritis were given Infliximab along with corticosteroids (before tapering them). No significant difference was observed in patients who were successfully tapered off corticosteroids. Moreover, few subjects had a higher infection rate with the use of Infliximab [14]. Use of Infliximab has shown great effectiveness in refractory Kawasaki disease [15]. Single-dose Infliximab (5 mg/kg) was given to seven patients who failed to achieve remission with the standard therapy. These patients showed improvement without any adverse effects [16]. In another study, good response was seen in two patients with Kawasaki disease when treated with Infliximab who had a relapse

This anti-TNF (tumor necrosis factor) agent has shown promising results in Wegener's granulomatosis in reducing the disease as well as inducing remission. Use of Infliximab is encouraged in medium vessel vasculitis. Patients with Kawasaki disease, who failed to respond to conventional therapy and those who experienced a relapse, reacted well to this agent. Unfortunately its use in giant cell arteritis is not promoted as suggested by a clinical study (as discussed above) in which patients with giant cell arteritis were treated with Infliximab showed no significant

**Table 4** summarizes the clinical outcomes of different studies and trials showing

Lamprecht et al. Infliximab WG Decrease in BVAS. No deaths, infections or

Randomized trial Infliximab GCA No significant difference. Increased rate of

Burns et al. Infliximab KD Improvement in patients who failed to achieve

adverse effects

remission by standard therapy/refractory disease

infection

adverse effects, deaths or infections were noted [13].

**Study Agent Disease Outcome**

response, instead resulted in a higher rate of infection.

effectiveness of Infliximab in different types of vasculitis.

**Study Agent Disease Outcome**

with the conventional therapy [17].


**Table 3.**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

disease [6].

maintenance [7].

received Rituximab [9].

3 months [10].

**3.2 Infliximab**

ment of Kawasaki disease [12].

remission was similar in both groups [8].

year, 14 patients were in sustained remission [11].

active vasculitis associated with rheumatoid arthritis.

Rituximab as treatment for systemic vasculitis.

In the Rituximab in ANCA-associated vasculitis (RAVE) trial, patients with GPA and MPA who were being given steroid therapy were randomized and received either oral cyclophosphamide or I/V Rituximab (four infusions). Patients who were given cyclophosphamide were switched to azathioprine after going into remission while those with Rituximab were switched to oral placebo. At the end of 6 months, Rituximab was found to be non-inferior to cyclophosphamide at inducing remission and was found to be superior to cyclophosphamide for patients with relapsing

Another study showed single course of Rituximab to be non-inferior to oral cyclophosphamide, which was followed by azathioprine for remission

In the Rituximab versus cyclophosphamide in ANCA-associated vasculitis (RITUXVAS) trial, where 44 patients were diagnosed with ANCA-associated vasculitis, patients were randomized to receive Rituximab along with only two infusions of cyclophosphamide. This was compared with patients who were given I/V cyclophosphamide for 3–6 months followed by azathioprine. The rate of sustained

These studies indicate that Rituximab is comparable in efficacy to cyclophosphamide for remission induction. Moreover, Maintenance of remission under Rituximab in systemic ANCA-associated vasculitis (MAINRITSAN) trial 115 patients with either GPA or MPA were given either azathioprine or Rituximab in a dose of 500 mg IV × 2 doses (after achieving remission with cyclophosphamide). At the end of the study, major relapse rate was significantly lower in patients who

Rituximab has also shown remarkable results in patients with EGPA whose disease was refractory to usual treatments (e.g. cyclophosphamide). One of the largest case series showed nine patients with EGPA refractory to conventional therapy, when treated with Rituximab were either in total or partial remission at the end of

The safety and efficacy of Rituximab has been evaluated by Puechal et al. in patients with active systemic rheumatoid vasculitis (SRV). Out of 17 patients with active SRV who were treated with Rituximab, 12 patients achieved complete remission of their disease at the end of 6 months. The Birmingham Vasculitis Activity Score (BVAS) for rheumatoid arthritis dropped down from a baseline of 9.6 to 0.6 and the daily average dose of Prednisolone declined from 19.2 to 9.7 mg. After a

Rituximab works by acting over B cells, clearing them from the body. It is the most extensively studied agent that has proved to be efficacious in most forms of vasculitis, especially ANCA-associated vasculitis. It is now the preferred choice over cyclophosphamide in order to reduce the adverse effect profile. Also, Rituximab is considered a suitable therapeutic option for inducing remission in patients with

**Table 3** summarizes the clinical outcomes of different trials carried out using

This is an IgG1, kappa monoclonal antibody specific for human tumor necrosis factor alpha. TNF alpha possesses multiple pro inflammatory properties for example, induction of Interleukin 1 and Interleukin 6, neutrophil activation etc. According to recent research, Infliximab is in phase 3 clinical development for treat-

**160**

*Rituximab trials [6, 8, 9].*

One clinical trial studied the role of Infliximab in granulomatosis with polyangiitis exclusively. These patients were followed even after the discontinuation of Infliximab to monitor the remission maintenance. The reduction of their Birmingham Vasculitis Activity Score was significant. Surprisingly no severe adverse effects, deaths or infections were noted [13].

Use of TNF alpha inhibitors is not encouraged in giant cell arteritis. In a randomized controlled trial, some newly diagnosed patients with giant cell arteritis were given Infliximab along with corticosteroids (before tapering them). No significant difference was observed in patients who were successfully tapered off corticosteroids. Moreover, few subjects had a higher infection rate with the use of Infliximab [14].

Use of Infliximab has shown great effectiveness in refractory Kawasaki disease [15]. Single-dose Infliximab (5 mg/kg) was given to seven patients who failed to achieve remission with the standard therapy. These patients showed improvement without any adverse effects [16]. In another study, good response was seen in two patients with Kawasaki disease when treated with Infliximab who had a relapse with the conventional therapy [17].

This anti-TNF (tumor necrosis factor) agent has shown promising results in Wegener's granulomatosis in reducing the disease as well as inducing remission. Use of Infliximab is encouraged in medium vessel vasculitis. Patients with Kawasaki disease, who failed to respond to conventional therapy and those who experienced a relapse, reacted well to this agent. Unfortunately its use in giant cell arteritis is not promoted as suggested by a clinical study (as discussed above) in which patients with giant cell arteritis were treated with Infliximab showed no significant response, instead resulted in a higher rate of infection.

**Table 4** summarizes the clinical outcomes of different studies and trials showing effectiveness of Infliximab in different types of vasculitis.


**Table 4.** *Infliximab trials [13–15].*

#### **3.3 Etanercept**

This is one of the most rigorously studied agent, which is also a tumor necrosis factor inhibitor. Its role has been studied in GPA and MPA for maintenance of remission. In WGET, 174 patients received methotrexate or cyclophosphamide for their remission and were then randomized to get Etanercept or placebo. Unfortunately, there was no significant difference in rate of sustained remission between Etanercept and placebo [18].

Etanercept (25 mg twice weekly) was given to 20 patients with Wegener's granulomatosis over a period of 6 months, in twice-daily dose. Out of these patients, 70% had never had remission of their disease. This drug was combined with either cyclophosphamide or methotrexate. During the treatment, 80% patients went into disease remission and their Birmingham Vasculitis Activity Score fell significantly. However, three patients experienced major flare despite the therapy [19, 20].

The major drawback is the increased incidence of cancer in patients treated with Etanercept. Six of 92 patients developed a solid tumor. These tumors included mucinous adenocarcinoma of colon, metastatic cholangiocarcinoma, renal cell carcinoma and breast carcinoma [21].

Wegener's granulomatosis itself is also associated with increased risk of malignancy. The specific malignancies associated with it are bladder carcinoma, squamous cell carcinoma, leukemia and lymphomas [22].

Use of these two agents (Infliximab and Etanercept) have shown promising results in Takayasu arteritis as demonstrated by a case series in which 15 patients with treatment resistant disease were treated with either of the drug. After introduction of these agents, the average dose of corticosteroid dropped from 20 mg (range 12.5–40 mg) to 0 mg (range 0–20 mg). Among these 15 patients 93% showed remarkable improvement and 67% experienced steroid free remission for up to 3 years [23].

Etanercept is one of the most widely studied agents, which is also an anti-TNF drug, and has been seen to be beneficial not only in ANCA-associated vasculitis but also in large vessel vasculitis (Takayasu arteritis). The biggest disadvantage of this medication is the higher incidence of different types of cancers.

**Table 5** summarizes two trials showing clinical outcomes of Etanercept in patients with Wegener's granulomatosis also known as granulomatosis with polyangiitis.

#### **3.4 Belimumab**

This is a human IgG1 gamma monoclonal antibody specific for soluble human B lymphocyte stimulator protein, also known as B cell-activating factor. Surprisingly, this is the only drug in late stage development for microscopic polyangiitis [12].

Currently this agent is in Phase 3 trial. Its efficacy and safety are being tested in a randomized, double blind study in combination with azathioprine. The dose given to patients is 10 mg/kg at days 0, 14, and 28 then after every 28 days till the study ends (clinical trials) [24].


**163**

*Treatment of Vasculitis: Beyond the Basics DOI: http://dx.doi.org/10.5772/intechopen.92729*

sion, reducing the use of steroid [25].

caused after discontinuing the medication.

tory to anti-TNF alpha therapy [29].

**3.5 Mepolizumab**

disease flare [26, 27].

**3.6 Tocilizumab**

pathways [28].

intravenous [30].

positive results in treatment of microscopic polyangiitis.

Belimumab is a relatively newer agent that is currently under trial but has shown

Mepolizumab is an Interleukin 5 humanized monoclonal antibody that binds to free Interleukin 5. It causes arrest of bone marrow eosinophil maturation. This monoclonal antibody is directed against Interleukin 5, which is a cytokine critical for activation of eosinophils. Mepolizumab when administered in a dose of 300 mg subcutaneously every 4 weeks, proved to be effective in prolonging disease remis-

Use of this agent has shown prompt normalization of peripheral eosinophil counts, as well as reduction in glucocorticoid usage. Two studies that showed use of Mepolizumab in EGPA, it led to decreased disease activity, normalization of eosinophil count and reduction of steroid use. However, cessation of this drug resulted in

Mepolizumab works by halting activation of eosinophils, acting directly on them. This biological agent is recommended in treating Churg-Strauss syndrome, although it is still under various trials. The major drawback is the disease flare

Tocilizumab is a humanized monoclonal antibody that binds to membranebound and soluble Interleukin 6 receptors and inhibits Interleukin 6 signaling

were refractory to Infliximab and three did not reach remission on steroids and methotrexate. Altogether eight patients received Tocilizumab and were followed for 18 months. Of these eight patients, seven achieved remission. This shows that Tocilizumab can be a potential therapy for patients with Takayasu arteritis refrac-

A study assessed eight patients who had refractory Takayasu arteritis. Two cases

A retrospective study assessed the effectiveness of Tocilizumab in complicated large vessel vasculitis. Patients were treated with Tocilizumab out of which eight had giant cell arteritis, two had large vessel vasculitis associated with rheumatoid arthritis and one had Takayasu arteritis. These patients were followed for 23 months. At the end of duration, seven patients were in remission, one patient relapsed after discontinuing the drug, and one patient suffered from serious infective complication. Two patients died, although cause of death was not attributable to the use of Tocilizumab. Three relapses occurred but remission was regained by switching the usual subcutaneous administration of Tocilizumab to

Glucocorticoids are the conventional treatment for giant cell arteritis but adverse effects are common, so are the relapses, soon after tapering the steroids. Although the exact cause of death is not known, cytokines such as tumor necrosis factor alpha and Interleukin 6 have been implicated. A retrospective study included 134 patients from 40 different centers who were diagnosed with giant cell arteritis either by temporal artery biopsy or imaging techniques. All these patients had received high dose of steroids in past and majority of patients had been given biologic immunosuppressives such as Abatacept, Infliximab or Rituximab. Tocilizumab was given either intravenously (8 mg/kg 4 weeks apart) or subcutaneously (162 mg/week). At the end of 1 month the ESR and CRP had fallen and percentage of patients with anemia had decreased. Those who were followed for 2 years, amongst them 39 were seen

**Table 5.** *Etanercept trials [18–20].*

Belimumab is a relatively newer agent that is currently under trial but has shown positive results in treatment of microscopic polyangiitis.
