Patients with recent or impending visual loss may be treated with initial pulsed intravenous doses of methylprednisolone (1,000 mg every day for three days) (Salvarani C et al., 2002). Corticosteroids may prevent but usually do not reverse visual loss.

Polymyalgia rheumatica can occur in 40% to 60% of patients with giant cell arteritis as a complication. Treatment with 10 to 20 mg/day prednisone can be effective in isolated polymyalgia rheumatica.

If the treatment does not result in improvement of symptoms, giant cell arteritis is suggested as an underlying disease (Langford CA, 2010).

To reduce significant steroid side effects or relapse on tapering the steroid dose, methotrexate is often added to the steroid (Hoffman GS et al., 2002; Jover JA et al., 2001; Mahr AD et al., 2007). A dose of 81 mg/day of aspirin has been reported to decrease the risk of cranial ischemic complications and all patients without a contraindication should be treated by aspirin together with prednisone (Lee MS et al., 2006; Nesher G et al., 2004).

Other drugs, such as cyclophosphamide, azathioprine, and etanercept, have been applied with variable success, although the success rates were generally less than hoped for success.

## **3. Takayasu arteritis**

Takayasu arteritis, which has also been known as the *aortic arch syndrome*, is an inflammatory and stenotic disease of medium- and large-sized arteries characterized by a strong predilection for the aortic arch and its branches (Langford CA & Fauci AS, 2008).

For the first 1 to 3 months, patients are treated with 1 mg/kg/day prednisone as an initial dose. After that, the dose is tapered to withdrawal over a 6- to 12-month period (Langford CA, 2010).

If the disease activity persists in spite of treatment with glucocorticoids or the dose of glucocorticoids cannot be tapered, cytotoxic therapy is primarily administrated (Langford CA, 2010). Doses of 15 to 25 mg/week methotrexate in combination with glucocorticoids may induce remission and minimize glucocorticoid therapy and toxicity in most of these patients (Hoffman GS et al., 1994). Azathioprine is used for the patients who are steroidresistant or have severe side effects by glucocorticoids. Cyclophosphamide has been used in patients with Takayasu arteritis refractory to glucocorticoids (Shelhamer JH et al., 1985). In the patients with intractable Takayasu arteritis, anti-TNF therapy may lead to durable remission in a majority of patients and facilitate dose reduction or discontinuation of prednisone and other immunosuppressive therapy (Molloy ES et al., 2008).

Vascular reconstructive surgery or angioplasty are adjunctive therapeautic options in some patients (Gota CE & Mandell BF, 2008).

## **4. Polyarteritis nodosa**

Polyarteritis nodosa constitutes a necrotizing inflammation of medium-sized or small arteries (Cox NH et al., 2010; Jennette JC et al., 1994). Polyarteritis nodosa does not show

40 mg/day is effective in more than 90% of patients (Hashimoto et al., 1999). After an initial dose of 60 mg/day, the dose can usually be decreased to 50 mg/day after 2 weeks and to 40 mg/day after 4 weeks (Langford CA, 2010). After clinical symptoms and laboratory data improve, the dose of prednisone was decreased by approximately 10% of the total daily

Patients with recent or impending visual loss may be treated with initial pulsed intravenous doses of methylprednisolone (1,000 mg every day for three days) (Salvarani C et al., 2002).

Polymyalgia rheumatica can occur in 40% to 60% of patients with giant cell arteritis as a complication. Treatment with 10 to 20 mg/day prednisone can be effective in isolated

If the treatment does not result in improvement of symptoms, giant cell arteritis is suggested

To reduce significant steroid side effects or relapse on tapering the steroid dose, methotrexate is often added to the steroid (Hoffman GS et al., 2002; Jover JA et al., 2001; Mahr AD et al., 2007). A dose of 81 mg/day of aspirin has been reported to decrease the risk of cranial ischemic complications and all patients without a contraindication should be treated by aspirin together with prednisone (Lee MS et al., 2006; Nesher G et al., 2004). Other drugs, such as cyclophosphamide, azathioprine, and etanercept, have been applied with variable success, although the success rates were generally less than hoped for

Takayasu arteritis, which has also been known as the *aortic arch syndrome*, is an inflammatory and stenotic disease of medium- and large-sized arteries characterized by a strong predilection for the aortic arch and its branches (Langford CA & Fauci AS, 2008). For the first 1 to 3 months, patients are treated with 1 mg/kg/day prednisone as an initial dose. After that, the dose is tapered to withdrawal over a 6- to 12-month period (Langford

If the disease activity persists in spite of treatment with glucocorticoids or the dose of glucocorticoids cannot be tapered, cytotoxic therapy is primarily administrated (Langford CA, 2010). Doses of 15 to 25 mg/week methotrexate in combination with glucocorticoids may induce remission and minimize glucocorticoid therapy and toxicity in most of these patients (Hoffman GS et al., 1994). Azathioprine is used for the patients who are steroidresistant or have severe side effects by glucocorticoids. Cyclophosphamide has been used in patients with Takayasu arteritis refractory to glucocorticoids (Shelhamer JH et al., 1985). In the patients with intractable Takayasu arteritis, anti-TNF therapy may lead to durable remission in a majority of patients and facilitate dose reduction or discontinuation of

Vascular reconstructive surgery or angioplasty are adjunctive therapeautic options in some

Polyarteritis nodosa constitutes a necrotizing inflammation of medium-sized or small arteries (Cox NH et al., 2010; Jennette JC et al., 1994). Polyarteritis nodosa does not show

prednisone and other immunosuppressive therapy (Molloy ES et al., 2008).

dose every 1 to 2 weeks (Salvarani C et al., 2002).

as an underlying disease (Langford CA, 2010).

polymyalgia rheumatica.

**3. Takayasu arteritis**

patients (Gota CE & Mandell BF, 2008).

**4. Polyarteritis nodosa**

success.

CA, 2010).

Corticosteroids may prevent but usually do not reverse visual loss.

glomerulonephritis or vasculitis in arterioles, capillaries or venules (Cox NH et al., 2010). Affected patients may have several signs and symptons involving multiple organ systems (Cox NH et al., 2010). Ischaemia, infarcts and haemorrhage result from the vasculitis and lead to end-organ damage in patient with polyarteritis nodosa (Cox NH et al., 2010).

Therapy for polyarteritis nodosa is still somewhat empiric. If patients have critical organ involvement, such as renal insufficiency, gastrointestinal ischemia, cardiomyopathy, dense peripheral neuropathy, or central nervous system involvement, they should be treated with 2 mg/kg/day cyclophosphamide and glucocorticoids (Gayraud M et al., 2001). In patients who do not have immediate critical organ involvement, glucocorticoids alone may be sufficient therapy. Patients who cannot taper glucocorticoids and are unresponsive to other therapy may be treated by cyclophosphamide with glucocorticoids (Langford CA, 2010).

In patients whose disease is strongly suspected to be caused by streptococcal infection and repeat recurrence, penicillin antibiotics may be given as preventive treatment. But it has not been reported that penicillin antibiotics alone are effective and the efficacy of this therapy has not been proved in randomized trials (Katsuoka K et al., 2008).

Nonsteroidal anti-inflammatory drugs may be administratered to polyarteritis nodosa patients with little or no evidence of systemic disease (Katsuoka K et al., 2008).

Vasodilator and antithrombotic agents may be used together with other drugs and have been especially promoted to be used in patients with skin ulcers and necrosis (Choi SW et al., 2006; Gonzalez-Fernandez MA & Garcia-Consuegra J, 2007; Lim MJ et al., 2006; Zulian F et al., 2004; Zulian F et al., 1998).

Dapsone and colchicines may be given to patients who are refractory to other therapy (Guillevin L, 1986; Thompson DM et al., 1976; Vignes S et al., 2005).

When active hepatitis B or C infection is present, an antiviral agent should be part of the treatment regimen, with the goal of containing viral replication and cause seroconversion (Langford CA, 2010).

Glucocorticoids, alone or combined with cyclophosphamide, might be given to patients in combination with apheresis (Guillevin L et al., 2005).

The possibility of drug-induced polyarteritis nodosa syndromes should always be considered. Propylthiouracil, hydralazine, leukotriene inhibitors, sulfasalazine, minocycline, D-penicillamine, ciprofloxacin, phenytoin, and allopurinol are included among the drugs that may cause these symptoms (Gota CE & Mandell BF, 2008).

#### **5. Wegener granulomatosis**

Wegener granulomatosis is a relatively uncommon, potentially lethal, and multisystem disease characterized by clinical disease involving the upper and lower respiratory tracts and kidneys with histological evidence of granulomatous inflammation, vasculitis of the small- to medium-sized vessels, and a pauci-immune glomerulonephritis (Hoffman GS et al., 1992).

Active Wegener granulomatosis is potentially life-threatening, therefore glucocorticoids combined with a cytotoxic agent are required as initial treatment. Patients with active severe Wegener granulomatosis should initially be treated with 2 mg/kg/day cyclophosphamide and simultaneously with prednisone at 1 mg/kg/day (Langford CA, 2010). After 4 weeks of

Treatment of Different Types of Vasculitis 79

mononeuritis multiplex (Pagnoux C, 2010). In ANCA-associated vasculitides, the prognosis of Churg-Strauss syndrome is better than those of Wegener granulomatosis and microscopic

Systemic administration of steroids is effective in Churg-Strauss syndrome, and many cases show remission by this therapy. Patients are treated by administration of 1 intravenous pulse of methylprednisolone (15 mg/kg) at the start of treatment (Ribi C et al., 2008). Oral prednisone (1 mg/kg/day) is given to patients for 3 weeks. After that, the dose is tapered slowly as the symptoms and laboratory data, especially the eosinophil

Cases that are steroid-resistant or relapse repeatedly by steroid treatment alone are additionally given 2 mg/kg/day cyclophosphamide or 50 to 100 mg/day azathioprine (Gayraud M et al., 2001). However, cyclophosphamide with glucocorticoids should be given early to patients with life-threatening disease (Gayraud M et al., 1997; Guillevin L et al., 1999; Guillevin L & Pagnoux C, 2003; Keogh KA & Specks U, 2006; Noth I et al., 2003; Solans R et al., 2001). To decrease the side effect of cyclophosphamide, cyclophosphamide pulse therapy is recommended (Cohen P et al., 2007; Gayraud M et al., 1997; Guillevin L &

Cutaneous vasculitis is a frequent and often significant component of many systemic vasculitic syndromes such as lupus or rheumatoid vasculitis and ANCA-associated primary vasculitic syndromes (Carlson JA et al., 2006). It is manifested as urticaria, purpura, hemorrhagic vesicles, ulcers, nodules, livedo, infarcts, or digital gangrene. In most instances, cutaneous vasculitis shows the features of a self-limiting, single-episode phenomenon.

If the patients have idiopathic cutaneous vasculitis, glucocorticoids are frequently used. Other drugs, such a nonsteroidal anti-inflammatory agents, antihistamines, dapsone, hydroxychloroquine, colchicines, and cyclophosphamide, may also be given to the patients.

Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins in serum. In the majority of cases of cryoglobulinaemia, the disease remains asymptomatic but immune complexes can form and be deposited in tissues, causing cryoglobulinemic

Asymptomatic cryoglobulinemia does not need to be treated. In symptomatic cryoglobulinemia, the treatment of the underlying disease can then proceed. If the underlying disease cannot be determined, it is idiopathic and symptomatic treatment is performed. It is important to determine the particular type of cryoglobulinemia, because the

Because type I cryoglobulins usually are associated with haematological disorders, these

Types II and III (mixed) cryoglobulinemias have strong connection with HCV infection (Braun GS et al., 2007). Aggressive antiviral therapy with Peg-IFNα and ribavirin provide

If the primary diseases or exposures are clarified, those are treated first.

polyangiitis (Guillevin L et al., 1999; Keogh KA & Specks U, 2006).

count, are improving.

Pagnoux C, 2003).

**8. Cutaneous vasculitis**

But there is no optimal dosage schedule.

vasculitis (Braun GS et al., 2007; Lamprecht P et al., 1999).

underlying disease may be associated with a particular type.

**9. Cryoglobulinemic vasculitis**

disorders are treated preferentially.

treatment, the prednisone is tapered and withdrawn by 6 to 12 months, if the treatment improves the patient's condition. Cyclophosphamide treatment for 3 to 6 months is performed, and then, cyclophosphamide is discontinued and the treatment is switched to a less toxic medication for remission maintenance (Langford CA, 2010). If patients have active but non-severe disease, the treatment by prednisone together with 20 to 25 mg/week methotrexate is effective at inducing and then maintaining remission (De Groot K et al., 2005).

It has been reported that the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse (Jayne D et al., 2003).

Treatment with trimethoprim–sulfamethoxazole (co-trimoxazole) reduces the incidence of relapse in patients with Wegener's granulomatosis in remission (Stegeman CA et al., 1996).

Plasma exchange increased the rate of renal recovery in patients that presented with renal failure (Jayne DR et al., 2007).

## **6. Microscopic polyangiitis**

Microscopic polyangiitis was originally considered to be a branch of polyarteritis nodosa; it includes glomerulonephritis and occasionally pulmonary hemorrhage. According to the Chapel Hill Consensus Conference in 1994, the definition of primary systemic vasculitis (PSV) has become clear, and the disease group included microscopic polyangiitis. Microscopic polyangiitis is a systemic necrotizing vasculitis affecting the small blood vessels or small- to medium-sized arteries.

2 mg/kg/day cyclophosphamide and 1 mg/kg/day prednisone should be given as initial therapy to patients who have life-threatening disease including lung, kidney, and nerve involvement (Langford CA, 2010). The therapy follows the schedule outlined for Wegener granulomatosis. It was reported that the combination therapy with cyclophosphamide and prednisone decreased the frequency of renal failure and recurrence (Hogan SL et al., 1996), and improved survival rates (Gayraud M et al., 2001). However, infectious events were strongly associated with the combination of corticosteroid and cyclophosphamide, and were more frequent in patients older than 65 years (Gayraud M et al., 2001). Moreover, cyclophosphamide increases the incidence rate of bladder cancer and induces gonadal failure dose-dependently. Therefore the remission induction should be followed by azathioprine or methotrexate administration for remission maintenance. Patients with active non-severe disease may be treated with methotrexate for remission and maintenance.

Mychophenolate mofetil (Villiger PM & Guillevin L, 2010), rituximab (Villiger PM & Guillevin L, 2010), trimethoprim-sulfamethoxazole (Jennette JC et al., 2001), plasma exchanges (Villiger PM & Guillevin L, 2010), intravenous immunoglobulins (Villiger PM & Guillevin L, 2010) can also be effective in microscopic polyangiitis, and etanercept has been recommended as well (Keogh KA et al., 2005).

#### **7. Churg-strauss syndrome**

Churg-Strauss syndrome is a rare systemic necrotizing vasculitis of small- to medium-sized vessels that was first described in the early 1950s. In patients with late-onset asthma it is characterized by vasculitic manifestations, such as fever, cutaneous purpura and

treatment, the prednisone is tapered and withdrawn by 6 to 12 months, if the treatment improves the patient's condition. Cyclophosphamide treatment for 3 to 6 months is performed, and then, cyclophosphamide is discontinued and the treatment is switched to a less toxic medication for remission maintenance (Langford CA, 2010). If patients have active but non-severe disease, the treatment by prednisone together with 20 to 25 mg/week methotrexate is effective at inducing and then maintaining remission (De Groot K et al.,

It has been reported that the withdrawal of cyclophosphamide and the substitution of

Treatment with trimethoprim–sulfamethoxazole (co-trimoxazole) reduces the incidence of relapse in patients with Wegener's granulomatosis in remission (Stegeman CA et al., 1996). Plasma exchange increased the rate of renal recovery in patients that presented with renal

Microscopic polyangiitis was originally considered to be a branch of polyarteritis nodosa; it includes glomerulonephritis and occasionally pulmonary hemorrhage. According to the Chapel Hill Consensus Conference in 1994, the definition of primary systemic vasculitis (PSV) has become clear, and the disease group included microscopic polyangiitis.  The therapy follows the schedule outlined for Wegener granulomatosis. It was reported that the combination therapy with cyclophosphamide and prednisone decreased the frequency of renal failure and recurrence (Hogan SL et al., 1996), and improved survival rates (Gayraud M et al., 2001). However, infectious events were strongly associated with the combination of corticosteroid and cyclophosphamide, and were more frequent in patients older than 65 years (Gayraud M et al., 2001). Moreover, cyclophosphamide increases the incidence rate of bladder cancer and induces gonadal failure dose-dependently. Therefore the remission induction should be followed by azathioprine or methotrexate administration for remission maintenance. Patients with active non-severe disease may be treated with methotrexate for remission and

Mychophenolate mofetil (Villiger PM & Guillevin L, 2010), rituximab (Villiger PM & Guillevin L, 2010), trimethoprim-sulfamethoxazole (Jennette JC et al., 2001), plasma exchanges (Villiger PM & Guillevin L, 2010), intravenous immunoglobulins (Villiger PM & Guillevin L, 2010) can also be effective in microscopic polyangiitis, and etanercept has been

Churg-Strauss syndrome is a rare systemic necrotizing vasculitis of small- to medium-sized vessels that was first described in the early 1950s. In patients with late-onset asthma it is characterized by vasculitic manifestations, such as fever, cutaneous purpura and

azathioprine after remission did not increase the rate of relapse (Jayne D et al., 2003).

2005).

failure (Jayne DR et al., 2007).

**6. Microscopic polyangiitis**

or small- to medium-sized arteries.

recommended as well (Keogh KA et al., 2005).

**7. Churg-strauss syndrome**

maintenance.

mononeuritis multiplex (Pagnoux C, 2010). In ANCA-associated vasculitides, the prognosis of Churg-Strauss syndrome is better than those of Wegener granulomatosis and microscopic polyangiitis (Guillevin L et al., 1999; Keogh KA & Specks U, 2006).

Systemic administration of steroids is effective in Churg-Strauss syndrome, and many cases show remission by this therapy. Patients are treated by administration of 1 intravenous pulse of methylprednisolone (15 mg/kg) at the start of treatment (Ribi C et al., 2008). Oral prednisone (1 mg/kg/day) is given to patients for 3 weeks. After that, the dose is tapered slowly as the symptoms and laboratory data, especially the eosinophil count, are improving.

Cases that are steroid-resistant or relapse repeatedly by steroid treatment alone are additionally given 2 mg/kg/day cyclophosphamide or 50 to 100 mg/day azathioprine (Gayraud M et al., 2001). However, cyclophosphamide with glucocorticoids should be given early to patients with life-threatening disease (Gayraud M et al., 1997; Guillevin L et al., 1999; Guillevin L & Pagnoux C, 2003; Keogh KA & Specks U, 2006; Noth I et al., 2003; Solans R et al., 2001). To decrease the side effect of cyclophosphamide, cyclophosphamide pulse therapy is recommended (Cohen P et al., 2007; Gayraud M et al., 1997; Guillevin L & Pagnoux C, 2003).

## **8. Cutaneous vasculitis**

Cutaneous vasculitis is a frequent and often significant component of many systemic vasculitic syndromes such as lupus or rheumatoid vasculitis and ANCA-associated primary vasculitic syndromes (Carlson JA et al., 2006). It is manifested as urticaria, purpura, hemorrhagic vesicles, ulcers, nodules, livedo, infarcts, or digital gangrene. In most instances, cutaneous vasculitis shows the features of a self-limiting, single-episode phenomenon.

If the primary diseases or exposures are clarified, those are treated first.

If the patients have idiopathic cutaneous vasculitis, glucocorticoids are frequently used. Other drugs, such a nonsteroidal anti-inflammatory agents, antihistamines, dapsone, hydroxychloroquine, colchicines, and cyclophosphamide, may also be given to the patients. But there is no optimal dosage schedule.

## **9. Cryoglobulinemic vasculitis**

Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins in serum. In the majority of cases of cryoglobulinaemia, the disease remains asymptomatic but immune complexes can form and be deposited in tissues, causing cryoglobulinemic vasculitis (Braun GS et al., 2007; Lamprecht P et al., 1999).

Asymptomatic cryoglobulinemia does not need to be treated. In symptomatic cryoglobulinemia, the treatment of the underlying disease can then proceed. If the underlying disease cannot be determined, it is idiopathic and symptomatic treatment is performed. It is important to determine the particular type of cryoglobulinemia, because the underlying disease may be associated with a particular type.

Because type I cryoglobulins usually are associated with haematological disorders, these disorders are treated preferentially.

Types II and III (mixed) cryoglobulinemias have strong connection with HCV infection (Braun GS et al., 2007). Aggressive antiviral therapy with Peg-IFNα and ribavirin provide

Treatment of Different Types of Vasculitis 81

Dapsone therapy may be useful for improving purpura and arthritis (Hoffbrand BI, 1991; Iqbal H & Evans A, 2005; Ramelli GP & Bianchetti MG, 1997; Sarma PS, 1994; Shimomura N

Kawasaki disease is an acute multisystem vasculitis of infants and young children. This disease represents the primary cause of acquired heart disease(Barron KS et al., 1999). For patients in the acute stage of the disease, a single high-dose intravenous immunoglobulin (2 g/kg) in combination with high-dose aspirin (80-100 mg/kg/day) is given (Muta H et al., 2004; Rowley AH & Shulman ST, 2010; Terai M & Shulman ST, 1997). However, patients in Asia are often treated with 80-100 mg/kg/day, because it is believed that 80-100 mg/kg/day of aspirin is excessively toxic in Asian children (Rowley AH & Shulman ST, 2010). Whether it is an advantage to add corticosteroid to this combination therapy is controversial (Inoue Y et al., 2006; Jibiki T et al., 2004; Newburger JW et al., 2007). About 5-15% of Kawasaki disease patients do not respond to this therapy. A second 2 g/kg dose of intravenous immunoglobulin and a 3-day course of intravenous pulsed methylprednisolone (30 mg/kg/day) can be effective in nonresponders (Freeman AF &

Administration of infliximab to these patients has been reported, but the efficacy is unclear

Low-dose aspirin (3-5 mg/kg/day) is given to the patients after the acute stage (Rowley AH & Shulman ST, 2010). In order to check the development of coronary aneurysms, an echocardiogram should be performed at 2, 6, and 8 weeks after illness onset (Langford CA, 2010). Close follow-up using ultrasonographic monitoring is needed for the patients with

Behçet disease is a multisystem inflammatory disease with an unknown etiology that affects all types and sizes of blood vessels (Calamia KT & Kaklamanis PG, 2008; Langford CA, 2010; Yazici Y et al., 2010). Treatment of Behçet disease is adjusted depending on the type and

Colchicine, 1.0-2.0 mg/day, can be effective for genital ulcers, erythema nodosum, and arthritis among women, although merely for arthritis in men (Yurdakul S et al., 2001). Azathioprine, 2.5 mg/kg/day, is able to prevent the progression of Behçet disease,

Cyclosporine is useful in treating ocular manifestations, oral aphthous ulcer, dermal lesions, and genital ulceration (Masuda K et al., 1989). Thalidomide, 100 mg/day, is effective for the

Interferon alpha-2a improves the duration and pain of oral ulcers and the frequency of

It was reported that tumor necrosis factor TNF α) antagonists, which are infliximab, etanercept, and adalimumab, improve symptoms in patients with eye, mucocutaneous, and gastrointestinal involvement, as well as neurological disease, and even pulmonary artery

Corticosteroids are widely used in the treatment of Behçet disease (Yazici Y et al., 2010).

oral and genital ulcers and papulopustular lesions (Hamuryudan V et al., 1998).

Shulman ST, 2004; Rowley AH & Shulman ST, 2010; Sundel RP et al., 1993).

multiple aneurysms, giant aneurysms, or coronary artery obstruction.

severity of symptoms, sex, and age (Yazici Y et al., 2010).

genital ulcers and papulopustular lesions (Alpsoy E et al., 2002).

particularly the eye disease (Yazici H et al., 1990).

aneurysms (Sfikakis PP et al., 2007).

(Burns JC et al., 2008; Burns JC et al., 2005).

**12. Behçet disease**

et al., 2005).

**11. Kawasaki disease**

the best opportunity for improvement of HCV-associated cryoglobulinemic vasculitis (Langford CA, 2010; Saadoun D et al., 2008).

Plasmapheresis is performed together with administration of corticosteroids and immunosuppressive drugs in order to prevent production of abnormal protein or to treat primary disease. But it is impractical for long-term treatment (Langford CA, 2010; Siami GA & Siami FS, 1999).

Rituximab, a chimeric monoclonal anti-CD20 antibody, is suitable as a rescue therapy in resistant cryoglobulinemia associated with HCV (Ahmed MS & Wong CF, 2007). Immunosuppressive agents are typically applied in patients with severe disease symptoms such as membranoproliferative glomerulonephritis, severe peripheral or central nervous system neuropathy, severe cutaneous disease, and vasculitis involving vital organs such as the heart or gastrointestinal tract (Vassilopoulos D & Calabrese LH, 2002). Immunosuppressive agents such as cyclophosphamide, azathioprine, cyclosporine, melphalan, chlorambucil, and fludarabine are usually used together with corticosteroids (Vassilopoulos D & Calabrese LH, 2002).

## **10. Henoch-schönlein purpura**

Henoch–Schönlein purpura is an acute, self-limited, systemic, small-vessel vasculitis. It predominantly affects children. Clinical presentation of Henoch–Schönlein purpura nephritis in adults is severe and the prognosis is relatively poor, worse than in children (Blanco R et al., 1997; Narchi H, 2005; Pillebout E et al., 2002). Therefore, more active treatment and careful follow up are needed in adults.

The treatment is not required in many cases of Henoch–Schönlein purpura because Henoch– Schönlein purpura is typically characterized by its self-limiting condition (Langford CA, 2010). Treatment with systemic application of glucocorticoids to patients with severe gastrointestinal symptoms is strongly recommended (Gunasekaran TS et al., 2000; Leung SP, 2001; Reinehr T et al., 2000; Ronkainen J et al., 2006). Prednisone does not prevent the development of renal symptoms but treats them effectively (Ronkainen J et al. reported that renal symptoms resolved in 61% of the prednisone-treated patients 80-100 mg/kg/day, compared with 34% of the placebo-receiving patients) (Ronkainen J et al., 2006). Moreover, methylprednisolone pulse therapy is effective in patients at risk of progression of nephropathy, particularly in the cases that started therapy early during the course of the disease before the crescents became fibrous (Niaudet P & Habib R, 1998).

The efficacy of immunosuppressive agents (e.g. cyclophosphamide, cyclosporin A), plasmapheresis, anticoagulant agents and antiplatelet agents is controversial.

Glucocorticoids in combination with each of these treatments can be effective in patients with severe nephritis (Flynn JT et al., 2001; Hattori M et al., 1999; Kawasaki Y et al., 2004; Ronkainen J et al., 2003; Scharer K et al., 1999; Someya T et al., 2004; Tanaka H et al., 2003; Tarshish P et al., 2004; Wyatt RJ & Hogg RJ, 2001; Zaffanello M et al., 2007).

Administration of Factor XIII, tonsillectomy, and dapsone may be useful for the patients with Henoch–Schönlein purpura, but the evidence concerning efficacy is insufficient. Factor XIII concentrate may contribute to abdominal pain relief in Henoch-Schönlein purpura patients (Shimomura N et al., 2005; Utani A et al., 1991).

Tonsillectomy may be useful for alleviating Henoch–Schönlein purpura nephropathy(Hotta O et al., 1996; Inoue CN et al., 2007; Sugiyama H et al., 2005; Tomioka S et al., 1996).

Dapsone therapy may be useful for improving purpura and arthritis (Hoffbrand BI, 1991; Iqbal H & Evans A, 2005; Ramelli GP & Bianchetti MG, 1997; Sarma PS, 1994; Shimomura N et al., 2005).

## **11. Kawasaki disease**

80 Advances in the Diagnosis and Treatment of Vasculitis

the best opportunity for improvement of HCV-associated cryoglobulinemic vasculitis

Plasmapheresis is performed together with administration of corticosteroids and immunosuppressive drugs in order to prevent production of abnormal protein or to treat primary disease. But it is impractical for long-term treatment (Langford CA, 2010; Siami GA

Rituximab, a chimeric monoclonal anti-CD20 antibody, is suitable as a rescue therapy in resistant cryoglobulinemia associated with HCV (Ahmed MS & Wong CF, 2007). Immunosuppressive agents are typically applied in patients with severe disease symptoms such as membranoproliferative glomerulonephritis, severe peripheral or central nervous system neuropathy, severe cutaneous disease, and vasculitis involving vital organs such as the heart or gastrointestinal tract (Vassilopoulos D & Calabrese LH, 2002). Immunosuppressive agents such as cyclophosphamide, azathioprine, cyclosporine, melphalan, chlorambucil, and fludarabine are usually used together with corticosteroids

Henoch–Schönlein purpura is an acute, self-limited, systemic, small-vessel vasculitis. It predominantly affects children. Clinical presentation of Henoch–Schönlein purpura nephritis in adults is severe and the prognosis is relatively poor, worse than in children (Blanco R et al., 1997; Narchi H, 2005; Pillebout E et al., 2002). Therefore, more active

The treatment is not required in many cases of Henoch–Schönlein purpura because Henoch– Schönlein purpura is typically characterized by its self-limiting condition (Langford CA, 2010). Treatment with systemic application of glucocorticoids to patients with severe gastrointestinal symptoms is strongly recommended (Gunasekaran TS et al., 2000; Leung SP, 2001; Reinehr T et al., 2000; Ronkainen J et al., 2006). Prednisone does not prevent the development of renal symptoms but treats them effectively (Ronkainen J et al. reported that renal symptoms resolved in 61% of the prednisone-treated patients 80-100 mg/kg/day, compared with 34% of the placebo-receiving patients) (Ronkainen J et al., 2006). Moreover, methylprednisolone pulse therapy is effective in patients at risk of progression of nephropathy, particularly in the cases that started therapy early during the course of the

The efficacy of immunosuppressive agents (e.g. cyclophosphamide, cyclosporin A),

Glucocorticoids in combination with each of these treatments can be effective in patients with severe nephritis (Flynn JT et al., 2001; Hattori M et al., 1999; Kawasaki Y et al., 2004; Ronkainen J et al., 2003; Scharer K et al., 1999; Someya T et al., 2004; Tanaka H et al., 2003;

Administration of Factor XIII, tonsillectomy, and dapsone may be useful for the patients with Henoch–Schönlein purpura, but the evidence concerning efficacy is insufficient. Factor XIII concentrate may contribute to abdominal pain relief in Henoch-Schönlein purpura

Tonsillectomy may be useful for alleviating Henoch–Schönlein purpura nephropathy(Hotta

O et al., 1996; Inoue CN et al., 2007; Sugiyama H et al., 2005; Tomioka S et al., 1996).

disease before the crescents became fibrous (Niaudet P & Habib R, 1998).

plasmapheresis, anticoagulant agents and antiplatelet agents is controversial.

Tarshish P et al., 2004; Wyatt RJ & Hogg RJ, 2001; Zaffanello M et al., 2007).

patients (Shimomura N et al., 2005; Utani A et al., 1991).

(Langford CA, 2010; Saadoun D et al., 2008).

(Vassilopoulos D & Calabrese LH, 2002).

treatment and careful follow up are needed in adults.

**10. Henoch-schönlein purpura**

& Siami FS, 1999).

Kawasaki disease is an acute multisystem vasculitis of infants and young children. This disease represents the primary cause of acquired heart disease(Barron KS et al., 1999).

For patients in the acute stage of the disease, a single high-dose intravenous immunoglobulin (2 g/kg) in combination with high-dose aspirin (80-100 mg/kg/day) is given (Muta H et al., 2004; Rowley AH & Shulman ST, 2010; Terai M & Shulman ST, 1997). However, patients in Asia are often treated with 80-100 mg/kg/day, because it is believed that 80-100 mg/kg/day of aspirin is excessively toxic in Asian children (Rowley AH & Shulman ST, 2010). Whether it is an advantage to add corticosteroid to this combination therapy is controversial (Inoue Y et al., 2006; Jibiki T et al., 2004; Newburger JW et al., 2007).

About 5-15% of Kawasaki disease patients do not respond to this therapy. A second 2 g/kg dose of intravenous immunoglobulin and a 3-day course of intravenous pulsed methylprednisolone (30 mg/kg/day) can be effective in nonresponders (Freeman AF & Shulman ST, 2004; Rowley AH & Shulman ST, 2010; Sundel RP et al., 1993).

Administration of infliximab to these patients has been reported, but the efficacy is unclear (Burns JC et al., 2008; Burns JC et al., 2005).

Low-dose aspirin (3-5 mg/kg/day) is given to the patients after the acute stage (Rowley AH & Shulman ST, 2010). In order to check the development of coronary aneurysms, an echocardiogram should be performed at 2, 6, and 8 weeks after illness onset (Langford CA, 2010). Close follow-up using ultrasonographic monitoring is needed for the patients with multiple aneurysms, giant aneurysms, or coronary artery obstruction.

### **12. Behçet disease**

Behçet disease is a multisystem inflammatory disease with an unknown etiology that affects all types and sizes of blood vessels (Calamia KT & Kaklamanis PG, 2008; Langford CA, 2010; Yazici Y et al., 2010). Treatment of Behçet disease is adjusted depending on the type and severity of symptoms, sex, and age (Yazici Y et al., 2010).

Colchicine, 1.0-2.0 mg/day, can be effective for genital ulcers, erythema nodosum, and arthritis among women, although merely for arthritis in men (Yurdakul S et al., 2001).

Azathioprine, 2.5 mg/kg/day, is able to prevent the progression of Behçet disease, particularly the eye disease (Yazici H et al., 1990).

Cyclosporine is useful in treating ocular manifestations, oral aphthous ulcer, dermal lesions, and genital ulceration (Masuda K et al., 1989). Thalidomide, 100 mg/day, is effective for the oral and genital ulcers and papulopustular lesions (Hamuryudan V et al., 1998).

Interferon alpha-2a improves the duration and pain of oral ulcers and the frequency of genital ulcers and papulopustular lesions (Alpsoy E et al., 2002).

It was reported that tumor necrosis factor TNF α) antagonists, which are infliximab, etanercept, and adalimumab, improve symptoms in patients with eye, mucocutaneous, and gastrointestinal involvement, as well as neurological disease, and even pulmonary artery aneurysms (Sfikakis PP et al., 2007).

Corticosteroids are widely used in the treatment of Behçet disease (Yazici Y et al., 2010).

Treatment of Different Types of Vasculitis 83

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Topical therapy, including glucocorticoids and sucralfate suspension, can be effective for aphthous lesions and mucocutaneous disease (Alpsoy E et al., 1999; Hatemi G et al., 2009). For patients in the early disease stages of pulmonary and peripheral arterial aneurysms, cyclophosphamide pulse therapy and corticosteroids are especially effective (Yazici Y et al., 2010).

#### **13. Acknowledgment**

We thank for Dr. Koichi Nakagawa, MD, Dr. Yasuhiko Yoshida, MD, Dr. Masaru Kishida, MD, Dr. Aya Kumei, MD, Dr. Takashi Hashimoto, MD, Dr. Hiromi Kobayashi, MD, PhD, and Dr. Masamitsu Ishii, MD, PhD for helping with the preparation of the paper.

#### **14. References**

Topical therapy, including glucocorticoids and sucralfate suspension, can be effective for aphthous lesions and mucocutaneous disease (Alpsoy E et al., 1999; Hatemi G et al., 2009). For patients in the early disease stages of pulmonary and peripheral arterial aneurysms, cyclophosphamide pulse therapy and corticosteroids are especially effective (Yazici Y et al.,

We thank for Dr. Koichi Nakagawa, MD, Dr. Yasuhiko Yoshida, MD, Dr. Masaru Kishida, MD, Dr. Aya Kumei, MD, Dr. Takashi Hashimoto, MD, Dr. Hiromi Kobayashi, MD, PhD,

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**5**

 *Greece*

**Treatment of ANCA – Associated Vasculitis**

*Department of Rheumatology, School of Medicine, University of Thessaly, Larissa,*

ANCA – associated vasculitis (AAV) encompass Wegener granulomatosus (WG), Churg Strauss syndrome (CSS) and Microscopic Polyangiitis (MPA). Granuloma formation characterizes both WG and CSS, while necrotising inflammation of middle to small arteries, pauci-immune glomerulonephritis and production of ANCA typify all three of them. Common clinical and laboratory features point towards common pathogenetic mechanisms and thus therapeutic approach have evolved over the years from treatment of individual members of the group to unified treatment strategies. It is the presentation of the disease rather than a particular AAV that guides treatment decisions. Clinical subtypes of AAV according to the extend and the severity of the disease, have been proposed by the European Vasculitis Study (EUVAS) Group (Jayne & Rasmussen 1997) (Table 1): AAV can be presented as localized, early systemic, generalized, severe or refractory disease. This classification currently serves as the basis for the assignment of different treatment

Forty years ago AAV was a rapidly fatal disease. One-year survival was estimated to be less than 20%, mainly due to pulmonary and/or renal failure and steroids-related infection (Hoffman et al. 1992). The introduction of oral cyclophosphamide (CyP) during the '70s radically changed the prognosis of AAV. Recent data from the EUVAS Group trials show that survival at 1-year is currently almost 90%. CyP in combination with prednisone remain today the cornerstone of treatment of AAV. However, several issues have emerged: a) there are still patients that either die early in the course of the disease or display progressive disease refractory to conventional treatment, b) relapses are frequent, affecting approximately 50% of patients with AAV during extended follow-up, c) the burden of drugrelated toxicity is high, as serious adverse events affect approximately 40% of the patients. In addition to glucocorticoids toxicity, CyP can acutely lead to cytopenias, hemorrhagic cystitis and infections along with late complications including gonadal insufficiency and

In an effort to minimize CyP toxicity as well as to find regimens that could replace CyP in cases of non-responding, refractory, or relapsing disease, several treatment options have been considered. During the last 20 years and despite the rarity of AAV, several multicenter, multi-national randomized control trials (RCTs) were conducted largely due to the combined efforts of EUVAS Group and the VCRC (Vasculitis Clinical Research Consortium), which have altered our treatment practice as it will be discussed below. Treatment of AAV consists of an initial phase aiming at rapid induction of remission and a

**1. Introduction**

regimens.

infertility, myelodysplasias and bladder cancer.

second phase where maintenance of remission is sought.

Christina G. Katsiari and Lazaros Sakkas

## **Treatment of ANCA – Associated Vasculitis**

Christina G. Katsiari and Lazaros Sakkas

*Department of Rheumatology, School of Medicine, University of Thessaly, Larissa, Greece*

#### **1. Introduction**

90 Advances in the Diagnosis and Treatment of Vasculitis

Yurdakul, S., Mat, C., Tuzun, Y., Ozyazgan, Y., Hamuryudan, V., Uysal, O., Senocak, M. &

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treatment of gangrene in systemic necrotizing vasculitis with iloprost. *Br J*

ANCA – associated vasculitis (AAV) encompass Wegener granulomatosus (WG), Churg Strauss syndrome (CSS) and Microscopic Polyangiitis (MPA). Granuloma formation characterizes both WG and CSS, while necrotising inflammation of middle to small arteries, pauci-immune glomerulonephritis and production of ANCA typify all three of them. Common clinical and laboratory features point towards common pathogenetic mechanisms and thus therapeutic approach have evolved over the years from treatment of individual members of the group to unified treatment strategies. It is the presentation of the disease rather than a particular AAV that guides treatment decisions. Clinical subtypes of AAV according to the extend and the severity of the disease, have been proposed by the European Vasculitis Study (EUVAS) Group (Jayne & Rasmussen 1997) (Table 1): AAV can be presented as localized, early systemic, generalized, severe or refractory disease. This classification currently serves as the basis for the assignment of different treatment regimens.

Forty years ago AAV was a rapidly fatal disease. One-year survival was estimated to be less than 20%, mainly due to pulmonary and/or renal failure and steroids-related infection (Hoffman et al. 1992). The introduction of oral cyclophosphamide (CyP) during the '70s radically changed the prognosis of AAV. Recent data from the EUVAS Group trials show that survival at 1-year is currently almost 90%. CyP in combination with prednisone remain today the cornerstone of treatment of AAV. However, several issues have emerged: a) there are still patients that either die early in the course of the disease or display progressive disease refractory to conventional treatment, b) relapses are frequent, affecting approximately 50% of patients with AAV during extended follow-up, c) the burden of drugrelated toxicity is high, as serious adverse events affect approximately 40% of the patients. In addition to glucocorticoids toxicity, CyP can acutely lead to cytopenias, hemorrhagic cystitis and infections along with late complications including gonadal insufficiency and infertility, myelodysplasias and bladder cancer.

In an effort to minimize CyP toxicity as well as to find regimens that could replace CyP in cases of non-responding, refractory, or relapsing disease, several treatment options have been considered. During the last 20 years and despite the rarity of AAV, several multicenter, multi-national randomized control trials (RCTs) were conducted largely due to the combined efforts of EUVAS Group and the VCRC (Vasculitis Clinical Research Consortium), which have altered our treatment practice as it will be discussed below. Treatment of AAV consists of an initial phase aiming at rapid induction of remission and a second phase where maintenance of remission is sought.

Treatment of ANCA – Associated Vasculitis 93

Following the paradigm of lupus nephritis, MMF has been examined whether it can replace CyP for the induction of remission in AAV. In a study including 35 patients with AAV renal vasculitis with serum creatinine <5.6 mg/dL, 18 received MMF (2g/day) and 17 monthly pulses of CyP (0.75–1.0 g/m2) for 6 months (Hu et al. 2008). According to the study, complete remission was achieved in 78% in the MMF group compared to 47% in the CyP group. Whether MMF truly bears superiority towards CyP remains to be verified in large controlled trilas. MYCYC (http://clinicaltrials.gov/ct2/show/ NCT00414128 (2010)), a multi-center controlled trial by EUVAS comparing the efficacy of MMF and CyP has been

Rituximab, an anti-CD20 chimeric monoclonal antibody that effectively depletes B cells, has recently received much attention regarding its treatment potential in AAV. The number of activated B cells in AAV is associated with disease activity and the extend of organ involvement. Moreover, B cells generate ANCA-producing plasma cells. Studies in humans and animal models support the concept that ANCA have a central role in the pathogenesis

The efficacy of rituximab to induce remission in generalized AAV was examined in two RCTs. In RITUXVAS trial (Jones et al. 2010), 11 patients received pulses CyP plus glucocorticoids and 33 patients additionally received rituximab. The rituximab group received four infusions of rituximab 375 mg/m2 per week plus two infusions of intravenous cyclophosphamide 15 mg/kg. The cyclophosphamide group received between six and ten infusions of cyclophosphamide 15 mg/kg. Azathioprine was used as maintenance therapy in all patients. At 12 months, remission rates were comparable between the two groups (76% for rituximab and 82% for CyP group). Rituximab (375 mg/m2 per week for four weeks) was also compared with oral CyP (2 mg/ kg per day) in addition to glucocorticoids in the RAVE trial (Stone et al. 2010). At 6 months remission rates were 64% for the rituximab and 53% for the CyP group. These lower rates of remission compared to other studies were probably due

Overall, both studies show that rituximab therapy is not inferior to CyP (oral or pulses) treatment for the induction of remission in patients with generilized AAV. It should be noted, however, that adverse effects were also comparable between rituximab and CyP receivers an issue that has to be further addressed in studies with extended follow-up. Rituximab can thus replace CyP treatment especially in patients where CyP is contraindicated and could be the drug of choice in patients with childbearing potential. In spring of 2011, rituximab became the

Early systemic AAV refers to patients with involvement of multiple sites but without

Following initial open label studies with promising results, the NORAM study (De Groot et al. 2005), a RCT initiated by EUVAS, evaluated the efficacy of MTX as a potentially less toxic than CyP alternative to induce remission in patients with early systemic AAV. In addition to corticosteroids, patients received either oral CyP (2 mg/Kg per day) or oral MTX (initial dose 15mg/week that was increased to 20-25mg/week) for 12 months. Patients' follow-up lasted 18 months, and during the last 6 months all medications were stopped. At 12 months remission rates between the two groups were comparable (89.8% for MTX and 93.5% for oral CyP). Time to remission in overall was also comparable. However, some patients with

initiated. Notably, MMF will be used at the increased dose of 3g/day.

and maintenance of AAV (Xiao et al. 2002)

to the aggressive tapering of corticosteroids employed.

first drug to get an FDA approval for the treatment of AAV.

**2.2 Early systemic AAV**

imminent renal or other vital organ failure.

Table 1. Clinical Subtypes of AAV according to the extend and the severity of the disease

## **2. Induction of remission**

The gold standard for induction of remission in most cases of AAV has been the combination of high dose prednisolone (1mg/kg/day with or without previous pulses 1g/d x 3d) with CyP either orally (2mg/kg/day) or intravenously (0.75 g/m2 every month for 6 months) (Adu et al. 1997; Guillevin et al. 1997). In order to reduce the cumulative dose of drugs and thus adverse effects, current treatment strategies are differentiated according to the presentation of the disease (Table 1) and along with different schemes of CyP administration include several other medications such as rituximab, mycophenolate mofetil (MMF) and methotrexate (MTX).

#### **2.1 Generalized AAV**

Generalized AAV refers to patients who display imminent vital organ failure or renal involvement with creatinine level below 5.6 mg/dL (500μmol/L).

In an earlier study including 47 patients with generalized AAV and renal involvement intravenous pulses of CyP (0.75 g/m2, monthly for 6 months) were equally effective in achieving remission as oral CyP. Moreover, fewer incidents of cytopenia and infections had been recorded in the pulse group (Haubitz & Schellong 1998).

A randomized controlled trial by EUVAS, termed CYCLOPS, compared another scheme of pulse cyclophosphamide with daily oral cyclophosphamide for the induction of remission of AAV (De Groot et al. 2009). Patients with generalized AAV (n=149) and renal involvement received prednisolone plus either pulse cyclophosphamide (15 mg/kg every 2-3 weeks; n *=* 76) or daily oral cyclophosphamide (2 mg/kg per day; n=73). The efficacy of both regimens was similar in inducing remission. Lower cumulative dose of CyP was achieved in the pulse group, which displayed fewer episodes of leukopenia. It should be noted though that following pulse treatment there was a tendency towards a higher rate of relapse compared to oral treatment during the 9-month follow-up of the study.

Although it is not clear whether there are significant differences regarding efficacy and safety between the 2 schemes of CyP pulses, EULAR recommendations endorse the following strategy (Mukhtyar et al. 2009): administration of 15mg/kg of CyP every 2 weeks for 3 pulses and then every 3 weeks for additional 3-6 pulses. According to the same set of recommendations prednisolone intake should start at 1mg/kg/day (or 60mg/day) for 1 month, tapered to 15mg/day at 3 months and 7.5mg/day at 12 months.

Early Systemic involvement of multiple sites but without

Table 1. Clinical Subtypes of AAV according to the extend and the severity of the disease

The gold standard for induction of remission in most cases of AAV has been the combination of high dose prednisolone (1mg/kg/day with or without previous pulses 1g/d x 3d) with CyP either orally (2mg/kg/day) or intravenously (0.75 g/m2 every month for 6 months) (Adu et al. 1997; Guillevin et al. 1997). In order to reduce the cumulative dose of drugs and thus adverse effects, current treatment strategies are differentiated according to the presentation of the disease (Table 1) and along with different schemes of CyP administration include several other medications such as rituximab, mycophenolate mofetil

Generalized AAV refers to patients who display imminent vital organ failure or renal

In an earlier study including 47 patients with generalized AAV and renal involvement intravenous pulses of CyP (0.75 g/m2, monthly for 6 months) were equally effective in achieving remission as oral CyP. Moreover, fewer incidents of cytopenia and infections had

A randomized controlled trial by EUVAS, termed CYCLOPS, compared another scheme of pulse cyclophosphamide with daily oral cyclophosphamide for the induction of remission of AAV (De Groot et al. 2009). Patients with generalized AAV (n=149) and renal involvement received prednisolone plus either pulse cyclophosphamide (15 mg/kg every 2-3 weeks; n *=* 76) or daily oral cyclophosphamide (2 mg/kg per day; n=73). The efficacy of both regimens was similar in inducing remission. Lower cumulative dose of CyP was achieved in the pulse group, which displayed fewer episodes of leukopenia. It should be noted though that following pulse treatment there was a tendency towards a higher rate of relapse

Although it is not clear whether there are significant differences regarding efficacy and safety between the 2 schemes of CyP pulses, EULAR recommendations endorse the following strategy (Mukhtyar et al. 2009): administration of 15mg/kg of CyP every 2 weeks for 3 pulses and then every 3 weeks for additional 3-6 pulses. According to the same set of recommendations prednisolone intake should start at 1mg/kg/day (or 60mg/day) for 1

involvement with creatinine level below 5.6 mg/dL (500μmol/L).

been recorded in the pulse group (Haubitz & Schellong 1998).

compared to oral treatment during the 9-month follow-up of the study.

month, tapered to 15mg/day at 3 months and 7.5mg/day at 12 months.

Generalized impending vital organ failure or renal involvement

Severe vital organ failure, typically renal involvement with

Refractory progressive disease despite conventional treatment

typically the upper respiratory track in WG

impending renal or other vital organ failure

with creatinine level below 5.6 mg/dL (500μmol/L)

serum creatinine over 5.6 mg/dL (500μmol/L)

**AAV Subtype Description**  Localized one system,

**2. Induction of remission**

(MMF) and methotrexate (MTX).

**2.1 Generalized AAV**

Following the paradigm of lupus nephritis, MMF has been examined whether it can replace CyP for the induction of remission in AAV. In a study including 35 patients with AAV renal vasculitis with serum creatinine <5.6 mg/dL, 18 received MMF (2g/day) and 17 monthly pulses of CyP (0.75–1.0 g/m2) for 6 months (Hu et al. 2008). According to the study, complete remission was achieved in 78% in the MMF group compared to 47% in the CyP group. Whether MMF truly bears superiority towards CyP remains to be verified in large controlled trilas. MYCYC (http://clinicaltrials.gov/ct2/show/ NCT00414128 (2010)), a multi-center controlled trial by EUVAS comparing the efficacy of MMF and CyP has been initiated. Notably, MMF will be used at the increased dose of 3g/day.

Rituximab, an anti-CD20 chimeric monoclonal antibody that effectively depletes B cells, has recently received much attention regarding its treatment potential in AAV. The number of activated B cells in AAV is associated with disease activity and the extend of organ involvement. Moreover, B cells generate ANCA-producing plasma cells. Studies in humans and animal models support the concept that ANCA have a central role in the pathogenesis and maintenance of AAV (Xiao et al. 2002)

The efficacy of rituximab to induce remission in generalized AAV was examined in two RCTs. In RITUXVAS trial (Jones et al. 2010), 11 patients received pulses CyP plus glucocorticoids and 33 patients additionally received rituximab. The rituximab group received four infusions of rituximab 375 mg/m2 per week plus two infusions of intravenous cyclophosphamide 15 mg/kg. The cyclophosphamide group received between six and ten infusions of cyclophosphamide 15 mg/kg. Azathioprine was used as maintenance therapy in all patients. At 12 months, remission rates were comparable between the two groups (76% for rituximab and 82% for CyP group). Rituximab (375 mg/m2 per week for four weeks) was also compared with oral CyP (2 mg/ kg per day) in addition to glucocorticoids in the RAVE trial (Stone et al. 2010). At 6 months remission rates were 64% for the rituximab and 53% for the CyP group. These lower rates of remission compared to other studies were probably due to the aggressive tapering of corticosteroids employed.

Overall, both studies show that rituximab therapy is not inferior to CyP (oral or pulses) treatment for the induction of remission in patients with generilized AAV. It should be noted, however, that adverse effects were also comparable between rituximab and CyP receivers an issue that has to be further addressed in studies with extended follow-up. Rituximab can thus replace CyP treatment especially in patients where CyP is contraindicated and could be the drug of choice in patients with childbearing potential. In spring of 2011, rituximab became the first drug to get an FDA approval for the treatment of AAV.

#### **2.2 Early systemic AAV**

Early systemic AAV refers to patients with involvement of multiple sites but without imminent renal or other vital organ failure.

Following initial open label studies with promising results, the NORAM study (De Groot et al. 2005), a RCT initiated by EUVAS, evaluated the efficacy of MTX as a potentially less toxic than CyP alternative to induce remission in patients with early systemic AAV. In addition to corticosteroids, patients received either oral CyP (2 mg/Kg per day) or oral MTX (initial dose 15mg/week that was increased to 20-25mg/week) for 12 months. Patients' follow-up lasted 18 months, and during the last 6 months all medications were stopped. At 12 months remission rates between the two groups were comparable (89.8% for MTX and 93.5% for oral CyP). Time to remission in overall was also comparable. However, some patients with

Treatment of ANCA – Associated Vasculitis 95

studies evaluated the therapeutic potential of infliximab revealing promising results. However, data derived from subsequent studies were conflicting and could not corroborate any additional benefit from the use of infliximab in patients with AAV (Booth et al. 2004; Josselin et al. 2008; Morgan et al. 2010). It should be noted that there is no RCT for infliximab in AAV. On the contrary, the effect of entanercept, another anti-TNF agent, was examined in a large RCT (WGET) with patients suffering from WG (Wegener's G.E.T.W. 2005). In WGET, etanercept was used as an additional therapy to standard treatment for the induction and maintenance of remission in 180 patients with WG. At 27 months, remission rates and timeto-remission, were not significantly different between the two groups. It should be emphasized that six patients in the etanercept group developed solid cancers compared to no such malignancies in the control group (Stone et al. 2006). Hence, etanercept is considered ineffective and potentially hazardous when added to standard therapy for induction and maintenance of remission in WG. The overall experience with anti-TNF drugs in AAV is either negative or inconclusive. Skepticism has replaced initial enthusiasm and

> Use IV methylprednisolone 500-1,000 mg/day for 3 days in critical organ

> mg/Kg/day) might be used adjusted

Use in non critical organ manifestations

Use in intolerance to CyP and in young patients with non-severe critical organ

manifestations

manifestations

cyclophosphamide

hemorrhage)

2 g/day In patients with moderate renal

Plasmapheresis Use in critical organ manifestations

Oral cyclophosphamide (2

to keep WBC >3,000/µL

(normal serum creatinine)

involvement who cannot take

(serum creatinine >5.6 mg/dL, lung

currently the use of TNF blockade in patients with AAV appears remote.

tapered to 15 mg/day at 3

15 mg/Kg 2-weekly for 3 pulses, then 3-weekly for 3-6

increased to 20-25 mg/week

**Drug Dosage Comments**

Prednisolone 60 mg/day for 1 month

Cyclophosphamide

Mycophenolate

Mofetil

IV pulse

months

pulses

Methotrexate Starting dose 15 mg/week,

Rituximab IV 375 mg/m2/week for 4 pulses

at 2 months

Table 2. Induction of remission in ANCA-associated vasculitis

pulmonary involvement or relatively extensive disease in the MTX group had delayed onset of remission. In addition, at 18 months the relapse rate in the MTX group was 69.5%, which was significantly higher compared to that observed in the CyP group (46.5%). These high relapse rates in both treatment arms suggest that treatment of early systemic AAV should last beyond 1 year. The overall frequency of adverse events did not differ between the two groups. Leukopenia was prevalent with the use of CyP as was liver dysfunction with the use of MTX. In view of the results of the NORAM study, EULAR recommend MTX as an alternative to CyP for remission induction in non-organ-threatening or non-life threatening AAV.

#### **2.3 Severe AAV**

Severe AAV refers to patients with vital organ failure, typically renal involvement with serum creatinine over 5.6 mg/dL (500μmol/L).

Patients with life- and/or vital organ threatening manifestations, such as diffuse alveolar hemorrhage (DAH), severe rapidly progressive glomerulonephritis (serum creatinine >5.6 mg/dL), glomerulonephritis with double serum positivity for MPO-ANCA and antiglomerular basement membrane antibodies (Rutgers et al. 2005), require urgent, aggressive treatment. Supportive measures such as blood transfusion and mechanical ventilation or hemodialysis are frequently required.

In a EUVAS trial called MEPEX (Jayne et al. 2007) the effectiveness of plasma exchange was evaluated in patients with severe AAV involving acute renal failure. All 137 patients received oral CyP and prednisolone. One group was assigned to additionally receive three infusions of 1g methylprednisolone pulse therapy (n=67) and a second to receive seven courses of plasma exchanges (n=70). At 3 months, 69% of patients who received plasma exchanges were alive and dialysis independent compared to the significantly lower 49% of patients treated with methylprednisolone pulses.

The usefulness of plasma exchange in patients already on dialysis at the time of diagnosis has also been suggested (de Lind et al. 2007). Intravenous pulses methylprednisolone as adjunctive therapy in patients with severe tubular atrophy and <18% normal glomeruli increased the chance of therapy-related death over the chance of dialysis independence. The same was true for the group receiving plasma exchange only when the proportion of normal glomeruli reached a value of <2%.

Although there are no RCT available, plasma exchanges appear to be warranted in patients with DAH. In a retrospective review of 20 patients with DAH that were presented at a single institute and were treated with plasma exchanges in addition to intravenous methylprednisolone with or without CyP, resolution of lung hemorrhage was achieved in all 20 patients after an average number of 6.4 treatments. Historical review of 11 patients hospitalized at the same centre and did not receive plasma exchanges revealed 3 deaths. (Klemmer Am J Kid Dis 2003).

#### **2.4 Other treatments**

Anti-Tumor Necrosis Factor (anti-TNF) regimens have been considered as an alternative to current treatment for over a decade. Based on the beneficial effects of TNF blockade in other chronic inflammatory disorders and the fact that several lines of evidence implicate TNF in the pathogenesis of AAV in humans and animal models of the disease, several small pilot

pulmonary involvement or relatively extensive disease in the MTX group had delayed onset of remission. In addition, at 18 months the relapse rate in the MTX group was 69.5%, which was significantly higher compared to that observed in the CyP group (46.5%). These high relapse rates in both treatment arms suggest that treatment of early systemic AAV should last beyond 1 year. The overall frequency of adverse events did not differ between the two groups. Leukopenia was prevalent with the use of CyP as was liver dysfunction with the use of MTX. In view of the results of the NORAM study, EULAR recommend MTX as an alternative to CyP for remission induction in non-organ-threatening or non-life threatening

Severe AAV refers to patients with vital organ failure, typically renal involvement with

Patients with life- and/or vital organ threatening manifestations, such as diffuse alveolar hemorrhage (DAH), severe rapidly progressive glomerulonephritis (serum creatinine >5.6 mg/dL), glomerulonephritis with double serum positivity for MPO-ANCA and antiglomerular basement membrane antibodies (Rutgers et al. 2005), require urgent, aggressive treatment. Supportive measures such as blood transfusion and mechanical ventilation or

In a EUVAS trial called MEPEX (Jayne et al. 2007) the effectiveness of plasma exchange was evaluated in patients with severe AAV involving acute renal failure. All 137 patients received oral CyP and prednisolone. One group was assigned to additionally receive three infusions of 1g methylprednisolone pulse therapy (n=67) and a second to receive seven courses of plasma exchanges (n=70). At 3 months, 69% of patients who received plasma exchanges were alive and dialysis independent compared to the significantly lower 49% of

The usefulness of plasma exchange in patients already on dialysis at the time of diagnosis has also been suggested (de Lind et al. 2007). Intravenous pulses methylprednisolone as adjunctive therapy in patients with severe tubular atrophy and <18% normal glomeruli increased the chance of therapy-related death over the chance of dialysis independence. The same was true for the group receiving plasma exchange only when the proportion of normal

Although there are no RCT available, plasma exchanges appear to be warranted in patients with DAH. In a retrospective review of 20 patients with DAH that were presented at a single institute and were treated with plasma exchanges in addition to intravenous methylprednisolone with or without CyP, resolution of lung hemorrhage was achieved in all 20 patients after an average number of 6.4 treatments. Historical review of 11 patients hospitalized at the same centre and did not receive plasma exchanges revealed 3 deaths.

Anti-Tumor Necrosis Factor (anti-TNF) regimens have been considered as an alternative to current treatment for over a decade. Based on the beneficial effects of TNF blockade in other chronic inflammatory disorders and the fact that several lines of evidence implicate TNF in the pathogenesis of AAV in humans and animal models of the disease, several small pilot

AAV.

**2.3 Severe AAV**

serum creatinine over 5.6 mg/dL (500μmol/L).

patients treated with methylprednisolone pulses.

hemodialysis are frequently required.

glomeruli reached a value of <2%.

(Klemmer Am J Kid Dis 2003).

**2.4 Other treatments**

studies evaluated the therapeutic potential of infliximab revealing promising results. However, data derived from subsequent studies were conflicting and could not corroborate any additional benefit from the use of infliximab in patients with AAV (Booth et al. 2004; Josselin et al. 2008; Morgan et al. 2010). It should be noted that there is no RCT for infliximab in AAV. On the contrary, the effect of entanercept, another anti-TNF agent, was examined in a large RCT (WGET) with patients suffering from WG (Wegener's G.E.T.W. 2005). In WGET, etanercept was used as an additional therapy to standard treatment for the induction and maintenance of remission in 180 patients with WG. At 27 months, remission rates and timeto-remission, were not significantly different between the two groups. It should be emphasized that six patients in the etanercept group developed solid cancers compared to no such malignancies in the control group (Stone et al. 2006). Hence, etanercept is considered ineffective and potentially hazardous when added to standard therapy for induction and maintenance of remission in WG. The overall experience with anti-TNF drugs in AAV is either negative or inconclusive. Skepticism has replaced initial enthusiasm and currently the use of TNF blockade in patients with AAV appears remote.

Table 2. Induction of remission in ANCA-associated vasculitis

Treatment of ANCA – Associated Vasculitis 97

day) or oral methotrexate (starting with 7.5 mg per week and reaching 20 mg per week after 8 weeks) for 2 years (Metzler et al. 2007). Leflunomide was more effective in preventing relapses than oral methotrexate (6 versus 13 relapses, respectively), but was associated with a higher rate of adverse events. However, this study was underpowered; it was initially

The potential benefit of MMF treatment for maintenance of remission in AAV has been demonstrated in preliminary uncontrolled studies (Silva et al. 2010). On the basis of these studies, an RCT by EUVAS, termed IMPROVE, comparing MMF with azathioprine for maintenance of remission in renal vasculitis, has been carried out (Hiemstra et al. 2010). Among 156 patients treated either with AZA (starting at 2 mg/kg/d) or MMF (starting at 2000 mg/d) following induction of remission with CyP and prednisolone, patients on MMF

Some observational studies provide preliminary data regarding the efficacy of other regimens to maintain remission in patients with AAV. Rituximab appears to be beneficial (Stasi et al. 2006; Rhee et al. 2010). A large RCT currently evaluates the efficacy of rituximab in comparison to AZA (MAINRITSAN , Study NCT00748644). On the contrary, addition of intravenous immunoglobulin (IVIg) to standard maintenance treatment (AZA plus

In overall, treatment with low-dose prednisolone plus AZA (2 mg/Kg/day until 12 months then 1.5 mg/Kg/day) (Jayne et al. 2003; Pagnoux et al. 2008), or MTX (20-25 mg/week) (Pagnoux et al. 2008) is currently the preferred approach for maintenance of remission in AAV. The duration of maintenance is not known but should be >24 months (Lapraik et al.

> Alternate-day schemes have also been applied to minimize side effects. Should probably be avoided in generalized or

> mg/Kg/day) might be used adjusted to keep WBC >3,000/µL in patients who

severe forms of the disease

Oral cyclophosphamide (1.5

experience frequent relapses

Waits to be compared with

Azathioprine

Currently the gold standard for maintenance of remission

At high doses is a good alternative to

Azathiprione. Should be considered in patients where AZA or MTX is either contraindicated or ineffective.

designed for 154 patients but only 54 were enrolled.

experienced more relapses compared to AZA group.

prednisone) does not prevent relapses (Fortin et al. 2009).

**Drug Dosage Comments**

at 12 months

months

months

Table 3. Maintenance of remission in ANCA-associated vasculitis

mg/day at 3 months tapered to 7.5 mg/day

0.75 mg/m2 every 3

months then 1.5 mg/kg/day

per week, increased to 25 mg per week

Prednisolone Starting from 15

Azathioprine 2 mg/kg/day for 12

Methotrexate Starting dose 0.3/kg

Rituximab IV 375 mg/m2 every 6

Maintenance treatment should last > 24 months

2007) (Table 3).

Cyclophosphamide

IV pulse

Since ANCA may have a central role in the pathogenesis of AAV, the idea to target autoreactive T cells that drive the production of ANCA excreeting-plasma cells appears to be a logical treatment approach. Abatacept, a CTLA4—Ig molecule, blocks the costimulatory talk between T and B cells and has been proven efficacious in the treatment of rheumatoid arthritis. A RCT to evaluate relapse rate over a 24 month period in patients treated for 12 months with abatacept in addition to standard treatment (MTX plus prednisone) had been initiated but unfortunately was recently terminated due to slow recruitment (ABAVAS Study NCT00482066).

Recent data generated increased interest towards the role of the complement pathway in the pathogenesis of AAV, which appears to have an essential role on how ANCA can damage the vascular wall. Eculizumab is a monoclonal antibody that blocks the activation of C5, a central component of the complement cascade. Blockade of C5 activation was shown to have substantial therapeutic effect in animal models of AAV. A similar approach to treat patients with AAV will be evaluated in a pilot study with 10 patients receiving eculizumab in addition to standard treatment (study NCT01275287).

In anticipation of novel treatments, drugs currently used to induce remission in AAV are summarized in Table 2 and include corticosteroids, CyP, MTX, MMF, Rituximab and plasmapheresis.

## **3. Maintenance of remission**

The majority of patients with AAV can achieve remission within the first 6 months of treatment. However, if no other care is undertaken over half of the patients may have a relapse within the first 2 years following remission (De Groot et al. 2005). Relapses in AAV were associated with subsequent progression to end-stage renal disease (Hogan et al. 2005). Moreover, the number of relapses for an individual patient was a strong predictor of damage during follow-up, as measured by the Vasculitis Damage Index (Koldingsnes & Nossent 2002). Therefore maintenance, once remission is achieved, is essential for the long term outcome of patients with AAV.

CyP as oral (1.5mg/kg per day) or infusion regimen (0.75/m2, effusion every 3 months) was initially the standard regimen to maintain remission (Hoffman et al. 1992). Because of the serious adverse events related to long term exposure to CyP less toxic drugs have been proposed such as azathioprine, methotrexate, leflunomide or MMF

The CYCAZAREM study by EUVAS randomly assigned 144 patients with AAV (who achieved remission with oral CyP and prednisolone) to receive either azathioprine (2 mg/kg per day; *n* = 71) or CyP (1.5 mg/kg per day; *n* = 73) (Jayne et al. 2003). Both treatment groups continued to receive prednisolone (7.5 mg per day). At 18 months of follow-up, relapses had occurred in 15.5% and 13.7% of patients in the azathioprine and CyP group, respectively, suggesting that azathioprine is as effective as CyP for maintaining remission in AAV. Adverse events were comparable between the two treatment groups.

In a RCT by the French Vasculitis Study Group, 126 patients with WG or MPA following induction therapy, were randomly assigned to receive either oral azathioprine (2 mg/kg per day; *n* = 63) or methotrexate (0.3 mg/kg per week, progressively increased to 25 mg per week; *n* = 63) for 12 months. No significant difference was found between the two groups in terms of relapse-free survival and toxicity at a follow-up period of 29 ± 13 months (Pagnoux et al. 2008).

In another RCT, 54 patients with WG (who achieved remission after treatment with cyclophosphamide and prednisolone) were randomly assigned oral leflunomide (30 mg per

Since ANCA may have a central role in the pathogenesis of AAV, the idea to target autoreactive T cells that drive the production of ANCA excreeting-plasma cells appears to be a logical treatment approach. Abatacept, a CTLA4—Ig molecule, blocks the costimulatory talk between T and B cells and has been proven efficacious in the treatment of rheumatoid arthritis. A RCT to evaluate relapse rate over a 24 month period in patients treated for 12 months with abatacept in addition to standard treatment (MTX plus prednisone) had been initiated but unfortunately was recently terminated due to slow

Recent data generated increased interest towards the role of the complement pathway in the pathogenesis of AAV, which appears to have an essential role on how ANCA can damage the vascular wall. Eculizumab is a monoclonal antibody that blocks the activation of C5, a central component of the complement cascade. Blockade of C5 activation was shown to have substantial therapeutic effect in animal models of AAV. A similar approach to treat patients with AAV will be evaluated in a pilot study with 10 patients receiving eculizumab in

In anticipation of novel treatments, drugs currently used to induce remission in AAV are summarized in Table 2 and include corticosteroids, CyP, MTX, MMF, Rituximab and

The majority of patients with AAV can achieve remission within the first 6 months of treatment. However, if no other care is undertaken over half of the patients may have a relapse within the first 2 years following remission (De Groot et al. 2005). Relapses in AAV were associated with subsequent progression to end-stage renal disease (Hogan et al. 2005). Moreover, the number of relapses for an individual patient was a strong predictor of damage during follow-up, as measured by the Vasculitis Damage Index (Koldingsnes & Nossent 2002). Therefore maintenance, once remission is achieved, is essential for the long

CyP as oral (1.5mg/kg per day) or infusion regimen (0.75/m2, effusion every 3 months) was initially the standard regimen to maintain remission (Hoffman et al. 1992). Because of the serious adverse events related to long term exposure to CyP less toxic drugs have been

The CYCAZAREM study by EUVAS randomly assigned 144 patients with AAV (who achieved remission with oral CyP and prednisolone) to receive either azathioprine (2 mg/kg per day; *n* = 71) or CyP (1.5 mg/kg per day; *n* = 73) (Jayne et al. 2003). Both treatment groups continued to receive prednisolone (7.5 mg per day). At 18 months of follow-up, relapses had occurred in 15.5% and 13.7% of patients in the azathioprine and CyP group, respectively, suggesting that azathioprine is as effective as CyP for maintaining remission in

In a RCT by the French Vasculitis Study Group, 126 patients with WG or MPA following induction therapy, were randomly assigned to receive either oral azathioprine (2 mg/kg per day; *n* = 63) or methotrexate (0.3 mg/kg per week, progressively increased to 25 mg per week; *n* = 63) for 12 months. No significant difference was found between the two groups in terms of relapse-free survival and toxicity at a follow-up period of 29 ± 13 months (Pagnoux

In another RCT, 54 patients with WG (who achieved remission after treatment with cyclophosphamide and prednisolone) were randomly assigned oral leflunomide (30 mg per

proposed such as azathioprine, methotrexate, leflunomide or MMF

AAV. Adverse events were comparable between the two treatment groups.

recruitment (ABAVAS Study NCT00482066).

plasmapheresis.

et al. 2008).

**3. Maintenance of remission**

term outcome of patients with AAV.

addition to standard treatment (study NCT01275287).

day) or oral methotrexate (starting with 7.5 mg per week and reaching 20 mg per week after 8 weeks) for 2 years (Metzler et al. 2007). Leflunomide was more effective in preventing relapses than oral methotrexate (6 versus 13 relapses, respectively), but was associated with a higher rate of adverse events. However, this study was underpowered; it was initially designed for 154 patients but only 54 were enrolled.

The potential benefit of MMF treatment for maintenance of remission in AAV has been demonstrated in preliminary uncontrolled studies (Silva et al. 2010). On the basis of these studies, an RCT by EUVAS, termed IMPROVE, comparing MMF with azathioprine for maintenance of remission in renal vasculitis, has been carried out (Hiemstra et al. 2010). Among 156 patients treated either with AZA (starting at 2 mg/kg/d) or MMF (starting at 2000 mg/d) following induction of remission with CyP and prednisolone, patients on MMF experienced more relapses compared to AZA group.

Some observational studies provide preliminary data regarding the efficacy of other regimens to maintain remission in patients with AAV. Rituximab appears to be beneficial (Stasi et al. 2006; Rhee et al. 2010). A large RCT currently evaluates the efficacy of rituximab in comparison to AZA (MAINRITSAN , Study NCT00748644). On the contrary, addition of intravenous immunoglobulin (IVIg) to standard maintenance treatment (AZA plus prednisone) does not prevent relapses (Fortin et al. 2009).

In overall, treatment with low-dose prednisolone plus AZA (2 mg/Kg/day until 12 months then 1.5 mg/Kg/day) (Jayne et al. 2003; Pagnoux et al. 2008), or MTX (20-25 mg/week) (Pagnoux et al. 2008) is currently the preferred approach for maintenance of remission in AAV. The duration of maintenance is not known but should be >24 months (Lapraik et al. 2007) (Table 3).

Maintenance treatment should last > 24 months

Table 3. Maintenance of remission in ANCA-associated vasculitis

Treatment of ANCA – Associated Vasculitis 99

There should be vigilance for side effects of drugs used (CyP, rituximab, MTX, IVIg, plasmapheresis). Patients should be checked for tuberculosis with chest x-rays and PPD skin test, and patients with latent tuberculosis should receive prophylaxis with isoniazid plus vitamin B6. Patients on IV pulse CyP, receive antiemetic drug (ondesarton) immediately prior to and 8 hours after the CyP pulse. On the day of IV CyP pulse, patients receive oral or IV hydration with 2-3 liters of fluid. They also receive IV 2-mercaptoethanesulfonate (mesna) (20% of CyP dose) immediately before and at 2, 4 and 8 hours after the CyP pulse to reduce irritation of urinary bladder. The dose of next IV CyP pulse is adjusted to keep nadir WBC (12-14 days after the IV pulse) >3,000/µL. The rate of leucopenia, infections, and gonadal toxicity is reduced in the IV pulse CyP compared to oral CyP regimen (De Groot et al. 2009; Haubitz & Schellong 1998). Oral mesna is also beneficial for patients on oral CyP. According to a recent study ever-tobacco smoking and previous episode of hemorrhagic cystitis were strong predictors for the development of cancer in the urinary tract. Thus

All patients receiving CyP are advised to take prophylaxis against Pneumocystis jiroveci with trimethoprime/sulphamethoxazole (800/160 mg thrice weekly). This may also prevent

Gonadal failure is a common side effect in patients treated with CyP, where the risk increases in parallel with the increase of the cumulative dose received. No standard care to preserve gonadal function has been proposed for patients with AAV under CyP. Similar issues encountered in patients with systemic lupus erythematosus (SLE) have been addressed. For women with SLE two protocols exist: administration of leuprolide acetate with or without transdermal estrogen and depo-progesterone for contraception. Leuprolide should be administered 10-14 days prior to each CyP infusion. In men with SLE, administration of intramuscular monthly injections of testosterone has been proposed. Analogous approaches should probably be established for young patients with

Patients on immunosuppression should not be vaccinated with live attenuated vaccines. They can and should be vaccinated with dead pathogens. Patients with WG exhibit adequate antibody (Holvast et al. 2009) and cell-mediated (Holvast ARD2010) immune

The treatment of ANCA-associated vasculitis (AAV) has evolved over the years from treatment of individual members of the group i.e Wegener granulomatosis(WG), Churg-Strauss syndrome (CSS), microscopic polyangiitis (MPA), to unified treatment. For years, treatment of WG was corticosteroids plus oral cyclophosphamide (CyP), which was effective but had a high frequency of severe adverse effects (Hoffman AIM1992). To reduce the adverse effects of CyP, notably, bone marrow suppression and infections, hemorrhagic cystitis, gonadal toxicity, and tumors, other regimens were sought. So, intense immunosuppression with CyP is used only for induction of remission, and then remission is maintained with drugs with fewer side effects, such as azathioprine (AZA) and

CyP dose should be adjusted for renal function and age.

patients with these characteristics need close surveillance.

response to influenza vaccines (Holvast et al. 2010).

relapses in patients with respiratory involvement (Zycinska et al. 2009).

**6.4 Precautions**

AAV at risk.

**7. Conclusion**

## **4. Relapse**

Symptoms and signs of apparent AAV relapse, especially in patients on immunosuppression, should be differentiated from infections and malignancies. Relapse can be treated with oral or IV pulses of CyP plus prednisolone (60 mg/day) (Wegener's G.E.T.W. 2005). Patients intolerant to CyP can receive MMF (Stassen et al. 2007) or rituximab. IVIg (added to maintenance treatment) can achieve remission (Martinez et al. 2008) and it is particularly useful until infection is ruled out.

## **5. Refractory disease**

Refractory disease refers to patients who experience progressive disease despite conventional treatment.

Patients with refractory disease should be treated in specialized centers. Rituximab has been successful in CyP-refractory disease in observational studies (Smith et al. 2006; Keogh et al. 2006; Jones et al. 2009; Keogh et al. 2005). Deoxyspergualin (0.5 mg/Kg/day subcutaneously in 6 cycles of 21 days with 7-day intervals), an antiproliferative agent licensed in Japan for acute renal transplant rejection, showed promise in phase II study (Flossmann et al. 2009). Infliximab was beneficial in refractory disease in observational studies (Josselin et al. 2008) but when added to standard induction treatment did not make any difference (Morgan et al. 2010).

## **6. Special issues**

## **6.1 End stage renal disease (ESRD) and renal transplantation**

Relapse of ANCA-associated vasculitis is significantly less frequent (0.08 episodes/personyear) in ESRD patients compared with patients with preserved renal function (0.16-0.20 episodes/person-year), but infection, an important cause of death is almost double in frequency in ESRD (Lionaki et al. 2009). Therefore, immunosuppression in patients with ESRD may be limited to patients with active vasculitis.

Patients with ESRD can receive renal transplants. The overall survival of renal transplants is 90% at 5 years (Gera et al. 2007), and 70% at 10 years (Little et al. 2009). In one study, risk factors for renal transplant rejection was transplantation <12 months postvasculitis remission (Little et al. 2009). Therefore, renal transplantation should be considered in patients with ESRD with sustained remission of vasculitis.

## **6.2 Subglottic stenosis**

Patients with active disease receive aggressive treatment with prednisolone and CyP, and tracheostomy, if needed. Rituximab may also be used in case of CyP inadequate response. In inactive disease, intralesional costicosteroid with dilatation is generally effective (Hernandez-Rodriguez et al. 2010).

#### **6.3 Orbital mass**

Aggressive treatment with steroids and CyP is the standard of care. Rituximab is effective in refractory cases

#### **6.4 Precautions**

98 Advances in the Diagnosis and Treatment of Vasculitis

Symptoms and signs of apparent AAV relapse, especially in patients on immunosuppression, should be differentiated from infections and malignancies. Relapse can be treated with oral or IV pulses of CyP plus prednisolone (60 mg/day) (Wegener's G.E.T.W. 2005). Patients intolerant to CyP can receive MMF (Stassen et al. 2007) or rituximab. IVIg (added to maintenance treatment) can achieve remission (Martinez et al.

Refractory disease refers to patients who experience progressive disease despite

Patients with refractory disease should be treated in specialized centers. Rituximab has been successful in CyP-refractory disease in observational studies (Smith et al. 2006; Keogh et al. 2006; Jones et al. 2009; Keogh et al. 2005). Deoxyspergualin (0.5 mg/Kg/day subcutaneously in 6 cycles of 21 days with 7-day intervals), an antiproliferative agent licensed in Japan for acute renal transplant rejection, showed promise in phase II study (Flossmann et al. 2009). Infliximab was beneficial in refractory disease in observational studies (Josselin et al. 2008) but when added to standard induction treatment did not make any difference (Morgan et al.

Relapse of ANCA-associated vasculitis is significantly less frequent (0.08 episodes/personyear) in ESRD patients compared with patients with preserved renal function (0.16-0.20 episodes/person-year), but infection, an important cause of death is almost double in frequency in ESRD (Lionaki et al. 2009). Therefore, immunosuppression in patients with

Patients with ESRD can receive renal transplants. The overall survival of renal transplants is 90% at 5 years (Gera et al. 2007), and 70% at 10 years (Little et al. 2009). In one study, risk factors for renal transplant rejection was transplantation <12 months postvasculitis remission (Little et al. 2009). Therefore, renal transplantation should be considered in

Patients with active disease receive aggressive treatment with prednisolone and CyP, and tracheostomy, if needed. Rituximab may also be used in case of CyP inadequate response. In inactive disease, intralesional costicosteroid with dilatation is generally effective

Aggressive treatment with steroids and CyP is the standard of care. Rituximab is effective in

2008) and it is particularly useful until infection is ruled out.

**6.1 End stage renal disease (ESRD) and renal transplantation**

ESRD may be limited to patients with active vasculitis.

patients with ESRD with sustained remission of vasculitis.

**4. Relapse**

**5. Refractory disease**

conventional treatment.

**6. Special issues**

**6.2 Subglottic stenosis**

**6.3 Orbital mass**

refractory cases

(Hernandez-Rodriguez et al. 2010).

2010).

CyP dose should be adjusted for renal function and age.

There should be vigilance for side effects of drugs used (CyP, rituximab, MTX, IVIg, plasmapheresis). Patients should be checked for tuberculosis with chest x-rays and PPD skin test, and patients with latent tuberculosis should receive prophylaxis with isoniazid plus vitamin B6. Patients on IV pulse CyP, receive antiemetic drug (ondesarton) immediately prior to and 8 hours after the CyP pulse. On the day of IV CyP pulse, patients receive oral or IV hydration with 2-3 liters of fluid. They also receive IV 2-mercaptoethanesulfonate (mesna) (20% of CyP dose) immediately before and at 2, 4 and 8 hours after the CyP pulse to reduce irritation of urinary bladder. The dose of next IV CyP pulse is adjusted to keep nadir WBC (12-14 days after the IV pulse) >3,000/µL. The rate of leucopenia, infections, and gonadal toxicity is reduced in the IV pulse CyP compared to oral CyP regimen (De Groot et al. 2009; Haubitz & Schellong 1998). Oral mesna is also beneficial for patients on oral CyP.

According to a recent study ever-tobacco smoking and previous episode of hemorrhagic cystitis were strong predictors for the development of cancer in the urinary tract. Thus patients with these characteristics need close surveillance.

All patients receiving CyP are advised to take prophylaxis against Pneumocystis jiroveci with trimethoprime/sulphamethoxazole (800/160 mg thrice weekly). This may also prevent relapses in patients with respiratory involvement (Zycinska et al. 2009).

Gonadal failure is a common side effect in patients treated with CyP, where the risk increases in parallel with the increase of the cumulative dose received. No standard care to preserve gonadal function has been proposed for patients with AAV under CyP. Similar issues encountered in patients with systemic lupus erythematosus (SLE) have been addressed. For women with SLE two protocols exist: administration of leuprolide acetate with or without transdermal estrogen and depo-progesterone for contraception. Leuprolide should be administered 10-14 days prior to each CyP infusion. In men with SLE, administration of intramuscular monthly injections of testosterone has been proposed. Analogous approaches should probably be established for young patients with AAV at risk.

Patients on immunosuppression should not be vaccinated with live attenuated vaccines. They can and should be vaccinated with dead pathogens. Patients with WG exhibit adequate antibody (Holvast et al. 2009) and cell-mediated (Holvast ARD2010) immune response to influenza vaccines (Holvast et al. 2010).

#### **7. Conclusion**

The treatment of ANCA-associated vasculitis (AAV) has evolved over the years from treatment of individual members of the group i.e Wegener granulomatosis(WG), Churg-Strauss syndrome (CSS), microscopic polyangiitis (MPA), to unified treatment. For years, treatment of WG was corticosteroids plus oral cyclophosphamide (CyP), which was effective but had a high frequency of severe adverse effects (Hoffman AIM1992). To reduce the adverse effects of CyP, notably, bone marrow suppression and infections, hemorrhagic cystitis, gonadal toxicity, and tumors, other regimens were sought. So, intense immunosuppression with CyP is used only for induction of remission, and then remission is maintained with drugs with fewer side effects, such as azathioprine (AZA) and

Treatment of ANCA – Associated Vasculitis 101

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Hogan, S.L., Falk, R.J., Chin, H., Cai, J., Jennette, C.E., Jennette, J.C. & Nachman, P.H. (2005)

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Holvast, A., Stegeman, C.A., Benne, C.A., Huckriede, A., Wilschut, J.C., Palache, A.M.,

Hu, W., Liu, C., Xie, H., Chen, H., Liu, Z. & LI, L. (2008) Mycophenolate mofetil versus

*Dialysis and Transplant Association-European Renal Association*, 23, pp. 1307. Jayne, D., Rasmussen, N., Andrassy, K., Bacon, P., Tervaert, J.W., DadonienJ., Ekstrand, A.,

Jayne, D.R., Gaskin, G., Rasmussen, N., Abramowicz, D., Ferrario, F., Guillevin, L.,

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