**5. Induction of remission**

#### **5.1. Glucocorticoids**

*Efficacy:* Glucocorticoids are the first line treatment to rapidly control inflammation and prevent further organ damage in patients with active AAV. There is no trial evidence to support the use, dose or route of steroids traditionally used in AAV but certainly experience has solidified their clinical use. In all the randomized trials glucocorticoids were used in combination with immunosuppressants and is it not possible to know their effect alone. A report in 1957 of 17 patients with PAN revealed that the use of glucocorticoids alone lead to 80% survival at 12 months compared to 64% in an untreated group [14]. However the superi‐ ority of cortisone was not maintained at 3 years [14, 15].

Calcium intake should fall in line with local treatment recommendations, and bisphosphonates are typically necessary for patients as they will be exposed to prolonged steroid use. Additional considerations are prophylaxis against opportunistic infections such as *Pneumocystis jiroveci* with Trimethoprim/Sulfamethoxazole (T/S), and stress-dose steroids for critical illness.

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193

*Efficacy:* Cyclophosphamide is typically reserved for patients with severe or generalized AAV, or if a poor prognostic factor is present. In 1973, Fauci and Wolff published their experience of treating 18 patients with GPA and systemic involvement with oral cyclophosphamide [21]. Twelve patients achieved remission, and 6 were able to discontinue immunosuppression after several months. They later reported on a larger cohort of 85 patients with GPA treated with a protocol of oral cyclophosphamide of 2 mg/kg/day and high dose prednisone of 1 mg/kg /day [22]. They were followed prospectively over 21 years with 93% achieving complete remission and a mean survival of 48 months although 29% relapsed. This work also highlighted the toxicity of this drug, such as gonadal failure, cystitis in 34% of patients, and 1 patient devel‐

In an effort to reduce the toxicity associated with the prolonged used of cyclophosphamide, Hoffman et al [23] designed a protocol of intravenous pulses, similar to the National Institute of Health (NIH) study of treatment of severe lupus nephritis [24]. Fourteen patients with GPA, 12 with relapsing disease previously treated with daily oral cyclophosphamide, received

glucocorticoids. If remission was achieved the pulses were reduced in frequency to every 2 months for 6 months then every 3 months for a total of 1.5 years. Glucocorticoids were tapered and stopped over this time period. Unfortunately, although 93% improved initially, only 21% had sustained remission. Thirty six percent (4 patients) had experienced toxicity, mostly attributable to infections, but confounded by the concomitant use of high doses of prednisone.

A subsequent 18 month European open-label randomized controlled multicenter clinical trial, CYCLOPS [16], of pulse versus daily oral cyclophosphamide in 149 newly diagnosed patients with AAV (including GPA, MPA and renal limited vasculitis) with renal involvement and a creatinine between 150 and 500 umol/L was performed. Patients in the intravenous pulse group received cyclophosphamide 15 mg/kg every 2 weeks for the first 3 pulses then continued either intravenous pulse (15 mg/kg) or oral pulse (5 mg/kg for 3 consecutive days), every 3 weeks afterwards until remission and then for another 3 months. The oral cyclophosphamide group received 2 mg/kg daily until remission then 1.5 mg/kg for another 3 months. Remission maintenance was with azathioprine at a dose of 2 mg/kg for 18 months. The cyclophosphamide doses were adjusted for renal function and age, as well as leukocyte count, with a maximum dose of 1.2 g in the pulse group and 200 mg in the daily oral group. Both groups were also treated with oral glucocorticoids during induction, with initially 1 mg/kg (maximum 80 mg)

used, but with progressive tapering to 12.5 mg at 3 months and 5 mg at 18 months.

of cyclophosphamide for 6 months along with high dose oral

**5.2. Induction of remission in generalized and severe AAV**

*5.2.1. Cyclophosphamide*

oping lymphoma.

monthly pulses of 1g/m2

In randomized controlled studies of remission induction, prednisone is started at 1 mg/kg then tapered to a low dose (e.g. 5 mg at 18 months in CYCLOPS) [16] or completely stopped at 12 months (NORAM) [17] or even 6 months (WGET [18], RAVE [19]). The complete weaning of steroids is not necessarily desirable as shown by a meta-analysis done by Walsh et al [20]. Continuation of low dose prednisone (5-7.5 mg/day) was associated with a lower relapse rate of 14% (95%CI 10-19%) compared to a relapse rate of 43% (95%CI 33-52%) in those with complete glucocorticoid discontinuation.

The European Vasculitis Study group (EUVAS) guidelines for the treatment of AAV [12] indicate that high dose prednisolone or prednisone at 1 mg/kg be used for the first month, then tapered to no less than 15 mg at 3 months and 10 mg or lower during the maintenance phase of treatment. In instances where rapid control of disease is necessary, parenteral methylpred‐ nisolone (1 g daily for 3 days) should be used in addition to oral glucocorticoids.

A clinical trial currently in progress named 'plasma exchange and glucocorticoid dosing in the treatment of ANCA-associated vasculitis' (PEXIVAS) (ClinicalTrials.gov Identifier: NCT00987389) will address the question of dose and tapering schedule of glucocorticoids. The trial design will compare the standard dosing of glucocorticoids (similar to the recommenda‐ tions of EUVAS) compared to a reduced dose regimen. All patients will receive between 1 and 3 g of intravenous methylprednisolone over 1 to 3 days, then daily oral glucocorticoid, which may consist of prednisone or prednisolone and administered through a weight-based protocol. Based on body weight, all participants will receive either 50, 60 or 75 mg/day of oral gluco‐ corticoid for 7 days. Participants in the standard-dose group will continue at 50, 60 or 75 mg/day for 7 additional days and taper to between 12.5 and 20 mg/day at 3 months and 5 mg/ day at 6 months. Participants in the low-dose group will continue at 25, 30 or 40 mg/day for 7 days and taper to between 6 and 10 mg/day by 3 months and 5 mg/day by 6 months. All patients will receive 5 mg/day from 6 months to 12 months after randomisation.

*Safety:* Multiple adverse consequences of steroid therapy are recognized, including weight gain and fat redistribution, fluid retention and hypertension, irritability and difficulty sleeping, cataracts and glaucoma, elevated blood sugars and skin thinning. It is critical to minimize steroid exposure while suppressing disease activity. It is common practice to prescribe therapy to reduce the risk of glucocorticoid-induced osteoporosis. Vitamin D supplementation and Calcium intake should fall in line with local treatment recommendations, and bisphosphonates are typically necessary for patients as they will be exposed to prolonged steroid use. Additional considerations are prophylaxis against opportunistic infections such as *Pneumocystis jiroveci* with Trimethoprim/Sulfamethoxazole (T/S), and stress-dose steroids for critical illness.

#### **5.2. Induction of remission in generalized and severe AAV**

#### *5.2.1. Cyclophosphamide*

**5. Induction of remission**

192 Updates in the Diagnosis and Treatment of Vasculitis

ority of cortisone was not maintained at 3 years [14, 15].

complete glucocorticoid discontinuation.

*Efficacy:* Glucocorticoids are the first line treatment to rapidly control inflammation and prevent further organ damage in patients with active AAV. There is no trial evidence to support the use, dose or route of steroids traditionally used in AAV but certainly experience has solidified their clinical use. In all the randomized trials glucocorticoids were used in combination with immunosuppressants and is it not possible to know their effect alone. A report in 1957 of 17 patients with PAN revealed that the use of glucocorticoids alone lead to 80% survival at 12 months compared to 64% in an untreated group [14]. However the superi‐

In randomized controlled studies of remission induction, prednisone is started at 1 mg/kg then tapered to a low dose (e.g. 5 mg at 18 months in CYCLOPS) [16] or completely stopped at 12 months (NORAM) [17] or even 6 months (WGET [18], RAVE [19]). The complete weaning of steroids is not necessarily desirable as shown by a meta-analysis done by Walsh et al [20]. Continuation of low dose prednisone (5-7.5 mg/day) was associated with a lower relapse rate of 14% (95%CI 10-19%) compared to a relapse rate of 43% (95%CI 33-52%) in those with

The European Vasculitis Study group (EUVAS) guidelines for the treatment of AAV [12] indicate that high dose prednisolone or prednisone at 1 mg/kg be used for the first month, then tapered to no less than 15 mg at 3 months and 10 mg or lower during the maintenance phase of treatment. In instances where rapid control of disease is necessary, parenteral methylpred‐

A clinical trial currently in progress named 'plasma exchange and glucocorticoid dosing in the treatment of ANCA-associated vasculitis' (PEXIVAS) (ClinicalTrials.gov Identifier: NCT00987389) will address the question of dose and tapering schedule of glucocorticoids. The trial design will compare the standard dosing of glucocorticoids (similar to the recommenda‐ tions of EUVAS) compared to a reduced dose regimen. All patients will receive between 1 and 3 g of intravenous methylprednisolone over 1 to 3 days, then daily oral glucocorticoid, which may consist of prednisone or prednisolone and administered through a weight-based protocol. Based on body weight, all participants will receive either 50, 60 or 75 mg/day of oral gluco‐ corticoid for 7 days. Participants in the standard-dose group will continue at 50, 60 or 75 mg/day for 7 additional days and taper to between 12.5 and 20 mg/day at 3 months and 5 mg/ day at 6 months. Participants in the low-dose group will continue at 25, 30 or 40 mg/day for 7

nisolone (1 g daily for 3 days) should be used in addition to oral glucocorticoids.

days and taper to between 6 and 10 mg/day by 3 months and 5 mg/day by 6 months. All patients will receive 5 mg/day from 6 months to 12 months after randomisation.

*Safety:* Multiple adverse consequences of steroid therapy are recognized, including weight gain and fat redistribution, fluid retention and hypertension, irritability and difficulty sleeping, cataracts and glaucoma, elevated blood sugars and skin thinning. It is critical to minimize steroid exposure while suppressing disease activity. It is common practice to prescribe therapy to reduce the risk of glucocorticoid-induced osteoporosis. Vitamin D supplementation and

**5.1. Glucocorticoids**

*Efficacy:* Cyclophosphamide is typically reserved for patients with severe or generalized AAV, or if a poor prognostic factor is present. In 1973, Fauci and Wolff published their experience of treating 18 patients with GPA and systemic involvement with oral cyclophosphamide [21]. Twelve patients achieved remission, and 6 were able to discontinue immunosuppression after several months. They later reported on a larger cohort of 85 patients with GPA treated with a protocol of oral cyclophosphamide of 2 mg/kg/day and high dose prednisone of 1 mg/kg /day [22]. They were followed prospectively over 21 years with 93% achieving complete remission and a mean survival of 48 months although 29% relapsed. This work also highlighted the toxicity of this drug, such as gonadal failure, cystitis in 34% of patients, and 1 patient devel‐ oping lymphoma.

In an effort to reduce the toxicity associated with the prolonged used of cyclophosphamide, Hoffman et al [23] designed a protocol of intravenous pulses, similar to the National Institute of Health (NIH) study of treatment of severe lupus nephritis [24]. Fourteen patients with GPA, 12 with relapsing disease previously treated with daily oral cyclophosphamide, received monthly pulses of 1g/m2 of cyclophosphamide for 6 months along with high dose oral glucocorticoids. If remission was achieved the pulses were reduced in frequency to every 2 months for 6 months then every 3 months for a total of 1.5 years. Glucocorticoids were tapered and stopped over this time period. Unfortunately, although 93% improved initially, only 21% had sustained remission. Thirty six percent (4 patients) had experienced toxicity, mostly attributable to infections, but confounded by the concomitant use of high doses of prednisone.

A subsequent 18 month European open-label randomized controlled multicenter clinical trial, CYCLOPS [16], of pulse versus daily oral cyclophosphamide in 149 newly diagnosed patients with AAV (including GPA, MPA and renal limited vasculitis) with renal involvement and a creatinine between 150 and 500 umol/L was performed. Patients in the intravenous pulse group received cyclophosphamide 15 mg/kg every 2 weeks for the first 3 pulses then continued either intravenous pulse (15 mg/kg) or oral pulse (5 mg/kg for 3 consecutive days), every 3 weeks afterwards until remission and then for another 3 months. The oral cyclophosphamide group received 2 mg/kg daily until remission then 1.5 mg/kg for another 3 months. Remission maintenance was with azathioprine at a dose of 2 mg/kg for 18 months. The cyclophosphamide doses were adjusted for renal function and age, as well as leukocyte count, with a maximum dose of 1.2 g in the pulse group and 200 mg in the daily oral group. Both groups were also treated with oral glucocorticoids during induction, with initially 1 mg/kg (maximum 80 mg) used, but with progressive tapering to 12.5 mg at 3 months and 5 mg at 18 months.

The administration route of cyclophosphamide did not affect the remission rate, with 88% of subjects randomized to pulse therapy and 88% of subjects randomized to daily oral therapy in remission at 9 months. Both groups had a median time to remission of 3 months (range of 0.5 to 8 months in the pulse group and 1 to 7.5 months in the daily oral group). The cumulative dose in the oral group was higher than the pulse group (median 15.9 g vs. 8.2 g) with a lower rate of leukopenia in the pulse group.

The long-term follow-up of these studies was recently reported [25]. Retrospective chart information was available for 134 out of 148 patients, and 1 patient was subsequently excluded as their diagnosis was changed to EGPA. The median follow-up was 4.3 years. An increased relapse rate was observed in the pulse group compared to the daily oral group. Fifteen (20.8%) of the daily oral group and 30 (39.5%) of the pulse group had at least one relapse. However there was no difference in survival, renal function nor adverse events between groups. The presence of PR3-ANCA was independently associated with an increase risk of relapse (hazard ratio 2.47 (95%CI 1.32-4.59, p=0.004).

A meta-analysis [26] of randomized trials [27-29] comparing daily oral versus intravenous pulse of cyclophosphamide concluded that pulse therapy was significantly less likely to fail in remission induction (odds ratio (OR) 0.29 (95% CI 0.12-0.73) and had a significantly lower risk of infection (OR: 0.45 (95% CI 0.23-0.89)) and leucopenia (OR 0.36 (95% CI 0.17-0.78)). There was a non-significant increase in the relapse odds in the pulse cyclophosphamide group (OR 1.79 (95%CI 0.85-3.75).

requiring a ventilator). The study was designed as a non-inferiority trial comparing intrave‐ nous rituximab (375 mg/m2 of body surface weekly for 4 weeks) to daily oral cyclophospha‐ mide (2mg/kg). Both groups received methylprednisolone 1 g for one to three pulses, followed by prednisone 1 mg/kg. The primary end point was defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) [35] of 0 and the complete discon‐ tinuation of prednisone at 6 months. Once remission was achieved by 3 to 6 months, mainte‐ nance therapy was initiated in the cyclophosphamide group with azathioprine (2 mg/kg), however the Rituximab group did not receive maintenance therapy. There was no difference in the primary outcome at 6 months between the 2 groups. Sixty-three of the 99 patients in the rituximab group (64%) reached the primary end point, as compared with 52 of 98 in the control group (53%), and met the criterion for non-inferiority (P<0.001). However, among patients with relapsing disease at baseline, rituximab was more efficacious than cyclophosphamide, with 34 of 51 patients in the rituximab group (67%) reaching the primary end point, as compared with only 21 of 50 in the control group (42%) (p=0.01). In an oral presentation at the American College of Rheumatology Annual Meeting in November 2011, the extended follow-up to 18 months was reported. One single course of rituximab without maintenance therapy was as effective as 18 months of induction and maintenance therapy with cyclophosphamide followed by azathioprine. Complete remission was achieved and sustained at 6, 12, and 18 months in 64%, 47%, and 39% of subjects in the rituximab arm, comparable at 53%, 39%, and 33% of subjects in the cyclophosphamide/azathioprine arm, respectively. Disease flares in the two treatment arms did not differ in number or severity, and no unexpected safety issues were detected. Patients at highest risk for flare had GPA, were PR3 positive, were without major renal disease, and had relapsing disease at baseline. Disease flares in the rituximab treated

**Age Creatinine Leukocyte nadir**

300 to 500 μmol/L (3.4 to 5.7 mg/dL) reduce pulse by 2.5

mg/kg

**Table 2.** Adjusted cyclophosphamide dose according to age, renal function and leukocyte count [16]

IV cyclosphamide: 15

>60: reduce dose by 2.5 mg/kg per pulse >70: reduce dose by 5 mg/kg per pulse

>60 reduce dose by

>70 reduce dose by

25%

50%

mg/kg Max dose: 1.2 g

Daily Oral cyclophosphamide

2 mg/kg

Max dose: 200 mg

**(10-14 days)**

2 to 3 x109/L reduce dose of subsequent pulse by 20% 1 to 2 x109/L reduce dose of subsequent pulse by 40%

**Leukocyte count**

195

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Treatment of ANCA-Associated Vasculitis in Adults

< 4x109/L stop drug

reduce dose by 25% <1x109/L restart at 50 mg then increase weekly as tolerated

until >4

subjects occurred only after the return of detectable levels of B cells.

RITUXVAS [34] was a European multicenter, open label, randomized trial of rituximab compared to intravenous cyclophosphamide in 44 patients with newly diagnosed ANCAassociatedvasculitis with renal involvement[34]. Subjects in the rituximab group receivedboth

*Safety:* Although cyclophosphamide has been the mainstay of treatment for generalized and severe forms of AAV, there are several limitations to its use. First, there are significant adverse events associated with this drug even at the lower cumulative dose achieved through pulse therapy. Infertility is a concern in individuals of childbearing age, and bladder toxicity and malignancy are associated with increased morbidity and mortality [30-32]. The development of leukopenia significantly increases the risk of bacterial infection, and renders the patient susceptible to opportunistic infections. Table 2 provides dose adjustment recommendations based on the patient's age, renal function and leukocyte nadir to reduce the risk of toxicity.

#### *5.2.2. Rituximab*

*Efficacy:* The use of Rituximab, an anti-CD20 monoclonal antibody depleting B lymphocytes, has been reported in several case series and case reports to be effective in patients with generalized, severe and refractory disease [33]. This was subsequently confirmed by 2 randomized controlled trials published in 2010, "Rituximab in ANCA-associated Vasculitis" (RAVE) [19] and "Randomised Trial of Rituximab Versus Cyclophosphamide for Generalized ANCA-Associated Vasculitis" (RITUXVAS) [34]. In these two studies rituximab was noninferior and/or equivalent to cyclophosphamide in inducing remission in AAV. Rituximab was superior to cyclophosphamide in relapsing patients.

RAVE [19] was a North American multicentre, randomized, double blind, controlled thera‐ peutic trial where 197 patients with new or relapsing ANCA positive GPA and MPA without severe renal disease (creatinine less than 354 umol/L) or severe alveolar hemorrhage (not


**Table 2.** Adjusted cyclophosphamide dose according to age, renal function and leukocyte count [16]

The administration route of cyclophosphamide did not affect the remission rate, with 88% of subjects randomized to pulse therapy and 88% of subjects randomized to daily oral therapy in remission at 9 months. Both groups had a median time to remission of 3 months (range of 0.5 to 8 months in the pulse group and 1 to 7.5 months in the daily oral group). The cumulative dose in the oral group was higher than the pulse group (median 15.9 g vs. 8.2 g) with a lower

The long-term follow-up of these studies was recently reported [25]. Retrospective chart information was available for 134 out of 148 patients, and 1 patient was subsequently excluded as their diagnosis was changed to EGPA. The median follow-up was 4.3 years. An increased relapse rate was observed in the pulse group compared to the daily oral group. Fifteen (20.8%) of the daily oral group and 30 (39.5%) of the pulse group had at least one relapse. However there was no difference in survival, renal function nor adverse events between groups. The presence of PR3-ANCA was independently associated with an increase risk of relapse (hazard

A meta-analysis [26] of randomized trials [27-29] comparing daily oral versus intravenous pulse of cyclophosphamide concluded that pulse therapy was significantly less likely to fail in remission induction (odds ratio (OR) 0.29 (95% CI 0.12-0.73) and had a significantly lower risk of infection (OR: 0.45 (95% CI 0.23-0.89)) and leucopenia (OR 0.36 (95% CI 0.17-0.78)). There was a non-significant increase in the relapse odds in the pulse cyclophosphamide group (OR

*Safety:* Although cyclophosphamide has been the mainstay of treatment for generalized and severe forms of AAV, there are several limitations to its use. First, there are significant adverse events associated with this drug even at the lower cumulative dose achieved through pulse therapy. Infertility is a concern in individuals of childbearing age, and bladder toxicity and malignancy are associated with increased morbidity and mortality [30-32]. The development of leukopenia significantly increases the risk of bacterial infection, and renders the patient susceptible to opportunistic infections. Table 2 provides dose adjustment recommendations based on the patient's age, renal function and leukocyte nadir to reduce the risk of toxicity.

*Efficacy:* The use of Rituximab, an anti-CD20 monoclonal antibody depleting B lymphocytes, has been reported in several case series and case reports to be effective in patients with generalized, severe and refractory disease [33]. This was subsequently confirmed by 2 randomized controlled trials published in 2010, "Rituximab in ANCA-associated Vasculitis" (RAVE) [19] and "Randomised Trial of Rituximab Versus Cyclophosphamide for Generalized ANCA-Associated Vasculitis" (RITUXVAS) [34]. In these two studies rituximab was noninferior and/or equivalent to cyclophosphamide in inducing remission in AAV. Rituximab was

RAVE [19] was a North American multicentre, randomized, double blind, controlled thera‐ peutic trial where 197 patients with new or relapsing ANCA positive GPA and MPA without severe renal disease (creatinine less than 354 umol/L) or severe alveolar hemorrhage (not

rate of leukopenia in the pulse group.

194 Updates in the Diagnosis and Treatment of Vasculitis

ratio 2.47 (95%CI 1.32-4.59, p=0.004).

1.79 (95%CI 0.85-3.75).

*5.2.2. Rituximab*

superior to cyclophosphamide in relapsing patients.

requiring a ventilator). The study was designed as a non-inferiority trial comparing intrave‐ nous rituximab (375 mg/m2 of body surface weekly for 4 weeks) to daily oral cyclophospha‐ mide (2mg/kg). Both groups received methylprednisolone 1 g for one to three pulses, followed by prednisone 1 mg/kg. The primary end point was defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) [35] of 0 and the complete discon‐ tinuation of prednisone at 6 months. Once remission was achieved by 3 to 6 months, mainte‐ nance therapy was initiated in the cyclophosphamide group with azathioprine (2 mg/kg), however the Rituximab group did not receive maintenance therapy. There was no difference in the primary outcome at 6 months between the 2 groups. Sixty-three of the 99 patients in the rituximab group (64%) reached the primary end point, as compared with 52 of 98 in the control group (53%), and met the criterion for non-inferiority (P<0.001). However, among patients with relapsing disease at baseline, rituximab was more efficacious than cyclophosphamide, with 34 of 51 patients in the rituximab group (67%) reaching the primary end point, as compared with only 21 of 50 in the control group (42%) (p=0.01). In an oral presentation at the American College of Rheumatology Annual Meeting in November 2011, the extended follow-up to 18 months was reported. One single course of rituximab without maintenance therapy was as effective as 18 months of induction and maintenance therapy with cyclophosphamide followed by azathioprine. Complete remission was achieved and sustained at 6, 12, and 18 months in 64%, 47%, and 39% of subjects in the rituximab arm, comparable at 53%, 39%, and 33% of subjects in the cyclophosphamide/azathioprine arm, respectively. Disease flares in the two treatment arms did not differ in number or severity, and no unexpected safety issues were detected. Patients at highest risk for flare had GPA, were PR3 positive, were without major renal disease, and had relapsing disease at baseline. Disease flares in the rituximab treated subjects occurred only after the return of detectable levels of B cells.

RITUXVAS [34] was a European multicenter, open label, randomized trial of rituximab compared to intravenous cyclophosphamide in 44 patients with newly diagnosed ANCAassociatedvasculitis with renal involvement[34]. Subjects in the rituximab group receivedboth rituximab (375 mg/m2 per week for 4 consecutive weeks) and intravenous cyclophosphamide (15 mg/kg) with the first and third rituximab infusions. They did not receive any maintenance therapy. If they had progressive disease within the first 6 months, a third dose of intravenous cyclophosphamidewaspermitted.Subjectsinthecontrolgroupreceivedintravenouscyclophos‐ phamide (15 mg/kg), every 2 weeks for the first three doses then every 3 weeks for 3 to 6 months until remission, followed by azathioprine for maintenance. Both treatment arms received 1 g of intravenous methylprednisolone and then oral prednisone at 1 mg/kg per day initially, with a reduction to 5 mg per day at the end of 6 months. The primary outcome was sustained remis‐ sion and rates of serious adverse events at 12 months. Thirty-three subjects were enrolled in the rituximab group and 11 in the control group. Sustained remission was observed in 25 of 33 patients in the rituximab group (76%) and 9 of 11 patients in the control group (82%) (p=0.68). Six of the 33 subjects in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died. Among the survivors, sustained remission rates at 12 months were equal, and observedin93%ofthe rituximabgroupand90%ofthe controlgroup(p= 0.80).Themediantime to remission was 90 days (interquartile range, 79 to 112) in the rituximab group and 94 days (interquartile range, 91 to 100) in the control group (p=0.87). At 12 months of follow-up, 4 of 27 subjects in the rituximab group (15%) and 1 of 10 subjects in the control group (10%) suffered a relapse (p=0.70). This study also demonstrated efficacy in serious renal disease. Among the 9 subjects who were on dialysis at study entry, 6 of the 8 subjects randomized to the rituximab group attained sustained remission, and 5 no longer required dialysis.

A study of patients with severe renal involvement of GPA and MPA causing rapidly progressive glomerulonephritis was designed to compare intravenous (IV) methylpredniso‐ lone and plasma exchange [38]. One hundred and thirty-seven patients with creatinine >500 umol/l were enrolled in this open label, randomized trial and 69% were on dialysis for less than 2 weeks at study entry. Both groups received oral cyclophosphamide (2.5 mg/kg/day reduced to 1.5 mg/kg/day at 3 months and stopped at 6 months), followed by azathio‐ prine (2 mg/kg/day). Oral prednisolone was tapered from 1 mg/kg/day at entry to 0.25 mg/ kg/day by week 10,15 mg/day at 3 months and10mg/day from 5 to12 months. The IV methylprednisolone group (n=67) received 1000 mg/day for three consecutive days, and the subjects in the plasma exchange group (n=70) underwent a total of seven plasma exchanges within 14 days of study entry, with a plasma exchange volume of 60 ml/kg on each occasion and volume replacement with 5% albumin mandated in the protocol. The primary outcome measure was renal recovery at 3 months, defined by patient survival,

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197

There was a significant decrease in the risk of end-stage renal disease in the plasma exchange group compared to IV methylprednisolone but there was no significant differ‐ ence in patient survival at 12 months. By 3 months, renal recovery had occurred in 33 (49%) of 67 of the IV methylprednisolone group and 48 (69%) of 70 of the plasma exchange group (95%CI for the difference 18 to 35%; p = 0.02). This effect was sustained to 12 months from entry with only two from each group progressing to end stage renal disease after initial recovery, with a risk reduction of 24% (95%CI 6.1 to 41) at 12 months. At 12 months, 43% of subjects in the IV methylprednisolone group and 59% of subjects in the plasma exchange group remained alive and independent of dialysis (p = 0.008). The hazard ratio for end stage renal disease over 12 months for plasma exchange versus IV methylpredniso‐ lone was 0.47 (95%CI 0.24 to 0.91; p = 0.03). Subject survival at 3 and 12 months respective‐ ly was 84% and 76% in the IV methylprednisolone group and 84% and 73% in the plasma exchange group (log rank test p = 0.68). Mortality was 25.5% at 12 months, and the major causes of death were infection (n = 19), pulmonary hemorrhage (n = 6), and cardiovascu‐ lar disease (n = 4). Most deaths occurred during the first 3 months, when corticosteroid dosages were highest and vasculitis was most active. After 3 months, there was a higher

The treatment of AAV with cyclophosphamide is associated with significant toxicity and morbidity as previously discussed. Alternative immunosuppression to reduce this risk have been studied. The "Non-Renal Wegener's Granulomatosis Treated Alternatively with Methotrexate" (NORAM) [17] trial was designed to test the hypothesis than methotrexate could replace cyclophosphamide for remission induction. NORAM was a non-inferiority, unblinded, prospective, randomized, controlled trial in early systemic GPA and MPA, without organ-threatening or life-threatening disease and a creatinine of less than 150 umol/

dialysis independence, and serum creatinine <500 umol/l (5.8 mg/dl).

mortality in those who had failed to recover renal function.

**5.3. Induction of remission in early systemic disease**

*5.3.1. Methotrexate*

*Safety:* Unfortunately, rituximab use was not associated with a lower rate of serious adverse events in either study, although there were more episodes of leukopenia in subjects random‐ ized to cyclophosphamide. In the RAVE study, there were no significant differences between the treatment groups in the numbers of total adverse events, serious adverse events, or non −disease related adverse events. During the first 6 months of the trial, solid malignant tumors were diagnosed in 1 patient in each group; 2 patients in the control group and 1 in the rituximab group died. Six malignant conditions developed in 5 additional patients after 6 months. Four of those patients had been assigned initially to rituximab and one had been assigned to cyclophosphamide. Among patients with exposure to rituximab during the trial, malignant conditions developed in 6 of 124 (5%), as compared with 1 of 73 patients without exposure to rituximab (1%, p=0.26). In RITUXVAS, severe adverse events were similar between groups (rituximab group 42% and 36% in the standard care group). Infection rates were similar (rituximab group incidence rate 0.66/patient year vs 0.60/patient year in the standard care group). Dialysis patients were particular prone to adverse events, with 3 of the 9 dying, and 7 of 9 with at least one serious adverse event.

#### *5.2.3. Plasma exchange*

The rationale for the physical removal of ANCA by plasma exchange is based on the demonstration of the pathogenic role of ANCA in animal models of AAV [36, 37]. Corticosteroids and cyclophosphamide are used concomitantly to suppress inflammation and autoantibody production.

A study of patients with severe renal involvement of GPA and MPA causing rapidly progressive glomerulonephritis was designed to compare intravenous (IV) methylpredniso‐ lone and plasma exchange [38]. One hundred and thirty-seven patients with creatinine >500 umol/l were enrolled in this open label, randomized trial and 69% were on dialysis for less than 2 weeks at study entry. Both groups received oral cyclophosphamide (2.5 mg/kg/day reduced to 1.5 mg/kg/day at 3 months and stopped at 6 months), followed by azathio‐ prine (2 mg/kg/day). Oral prednisolone was tapered from 1 mg/kg/day at entry to 0.25 mg/ kg/day by week 10,15 mg/day at 3 months and10mg/day from 5 to12 months. The IV methylprednisolone group (n=67) received 1000 mg/day for three consecutive days, and the subjects in the plasma exchange group (n=70) underwent a total of seven plasma exchanges within 14 days of study entry, with a plasma exchange volume of 60 ml/kg on each occasion and volume replacement with 5% albumin mandated in the protocol. The primary outcome measure was renal recovery at 3 months, defined by patient survival, dialysis independence, and serum creatinine <500 umol/l (5.8 mg/dl).

There was a significant decrease in the risk of end-stage renal disease in the plasma exchange group compared to IV methylprednisolone but there was no significant differ‐ ence in patient survival at 12 months. By 3 months, renal recovery had occurred in 33 (49%) of 67 of the IV methylprednisolone group and 48 (69%) of 70 of the plasma exchange group (95%CI for the difference 18 to 35%; p = 0.02). This effect was sustained to 12 months from entry with only two from each group progressing to end stage renal disease after initial recovery, with a risk reduction of 24% (95%CI 6.1 to 41) at 12 months. At 12 months, 43% of subjects in the IV methylprednisolone group and 59% of subjects in the plasma exchange group remained alive and independent of dialysis (p = 0.008). The hazard ratio for end stage renal disease over 12 months for plasma exchange versus IV methylpredniso‐ lone was 0.47 (95%CI 0.24 to 0.91; p = 0.03). Subject survival at 3 and 12 months respective‐ ly was 84% and 76% in the IV methylprednisolone group and 84% and 73% in the plasma exchange group (log rank test p = 0.68). Mortality was 25.5% at 12 months, and the major causes of death were infection (n = 19), pulmonary hemorrhage (n = 6), and cardiovascu‐ lar disease (n = 4). Most deaths occurred during the first 3 months, when corticosteroid dosages were highest and vasculitis was most active. After 3 months, there was a higher mortality in those who had failed to recover renal function.

#### **5.3. Induction of remission in early systemic disease**

#### *5.3.1. Methotrexate*

rituximab (375 mg/m2

196 Updates in the Diagnosis and Treatment of Vasculitis

per week for 4 consecutive weeks) and intravenous cyclophosphamide

(15 mg/kg) with the first and third rituximab infusions. They did not receive any maintenance therapy. If they had progressive disease within the first 6 months, a third dose of intravenous cyclophosphamidewaspermitted.Subjectsinthecontrolgroupreceivedintravenouscyclophos‐ phamide (15 mg/kg), every 2 weeks for the first three doses then every 3 weeks for 3 to 6 months until remission, followed by azathioprine for maintenance. Both treatment arms received 1 g of intravenous methylprednisolone and then oral prednisone at 1 mg/kg per day initially, with a reduction to 5 mg per day at the end of 6 months. The primary outcome was sustained remis‐ sion and rates of serious adverse events at 12 months. Thirty-three subjects were enrolled in the rituximab group and 11 in the control group. Sustained remission was observed in 25 of 33 patients in the rituximab group (76%) and 9 of 11 patients in the control group (82%) (p=0.68). Six of the 33 subjects in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died. Among the survivors, sustained remission rates at 12 months were equal, and observedin93%ofthe rituximabgroupand90%ofthe controlgroup(p= 0.80).Themediantime to remission was 90 days (interquartile range, 79 to 112) in the rituximab group and 94 days (interquartile range, 91 to 100) in the control group (p=0.87). At 12 months of follow-up, 4 of 27 subjects in the rituximab group (15%) and 1 of 10 subjects in the control group (10%) suffered a relapse (p=0.70). This study also demonstrated efficacy in serious renal disease. Among the 9 subjects who were on dialysis at study entry, 6 of the 8 subjects randomized to the rituximab

*Safety:* Unfortunately, rituximab use was not associated with a lower rate of serious adverse events in either study, although there were more episodes of leukopenia in subjects random‐ ized to cyclophosphamide. In the RAVE study, there were no significant differences between the treatment groups in the numbers of total adverse events, serious adverse events, or non −disease related adverse events. During the first 6 months of the trial, solid malignant tumors were diagnosed in 1 patient in each group; 2 patients in the control group and 1 in the rituximab group died. Six malignant conditions developed in 5 additional patients after 6 months. Four of those patients had been assigned initially to rituximab and one had been assigned to cyclophosphamide. Among patients with exposure to rituximab during the trial, malignant conditions developed in 6 of 124 (5%), as compared with 1 of 73 patients without exposure to rituximab (1%, p=0.26). In RITUXVAS, severe adverse events were similar between groups (rituximab group 42% and 36% in the standard care group). Infection rates were similar (rituximab group incidence rate 0.66/patient year vs 0.60/patient year in the standard care group). Dialysis patients were particular prone to adverse events, with 3 of the 9 dying, and 7

The rationale for the physical removal of ANCA by plasma exchange is based on the demonstration of the pathogenic role of ANCA in animal models of AAV [36, 37]. Corticosteroids and cyclophosphamide are used concomitantly to suppress inflammation

group attained sustained remission, and 5 no longer required dialysis.

of 9 with at least one serious adverse event.

*5.2.3. Plasma exchange*

and autoantibody production.

The treatment of AAV with cyclophosphamide is associated with significant toxicity and morbidity as previously discussed. Alternative immunosuppression to reduce this risk have been studied. The "Non-Renal Wegener's Granulomatosis Treated Alternatively with Methotrexate" (NORAM) [17] trial was designed to test the hypothesis than methotrexate could replace cyclophosphamide for remission induction. NORAM was a non-inferiority, unblinded, prospective, randomized, controlled trial in early systemic GPA and MPA, without organ-threatening or life-threatening disease and a creatinine of less than 150 umol/ L. More than 90% of patients had GPA. In total, 49 subjects were treated with methotrex‐ ate (15 mg/week orally escalating to a maximum of 20–25 mg/week by 12 weeks), which was then maintained until month 10 and then tapered and discontinued by month 12. A total of 46 subjects received oral cyclophosphamide (2 mg/kg/day (maximum 150 mg/ day) until remission), for a minimum of 3 and a maximum of 6 months. Dose alterations were made for subjects >60 years of age, and the drug was withdrawn if the total white blood cell count fell below 4 x109 /liter. At remission, cyclophosphamide was reduced to 1.5 mg/kg/day until month 10, when it was tapered and discontinued by month 12. Both treatment groups received oral prednisolone 1 mg/kg/day, tapered to 15 mg/day at 12 weeks and 7.5 mg/day by 6 months, and discontinued by 12 months. The primary end point was induction of remission within 6 months. Between month 12 to 18, patients received no immunosuppressant agents.

**6. Maintenance of remission**

for maintenance of remission.

**6.1. Azathioprine**

**6.2. Methotrexate**

The relapse rate of AAV is high, as demonstrated by the different induction trials, and occur frequently during a drug withdrawal period [32, 39]. Therefore it is important to maintain long-term immunosuppression, while limiting drug toxicity. When a standardized treatment of induction of remission followed by maintenance therapy is applied, the relapse rate in GPA can be reduced from 76.8% (in cohorts treated before 1993) to 50% (in cohorts treated after 1999) over 5 years follow-up [40]. Several studies have provided different drug alternatives

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199

An 18 month prospective open label study (CYCAZAREM) compared the use of oral cyclo‐ phosphamide to azathioprine in the maintenance phase, with 155 subjects with GPA, MPA and renal limited vasculitis recruited from 39 hospitals in 11 European countries [41]. All subjects had received the same remission-induction therapy, consisting of daily oral cyclo‐ phosphamide (2 mg/kg) and prednisolone (initially 1 mg/kg/day, with the dose tapered to 0.25 mg/kg/day by 12 weeks). Renal vasculitis was the most common form of organ involvement, occurring in 94 percent of the patients in the study. Patients attaining remission by 3 months, and those attaining remission between 3 and 6 months, were randomly assigned to treatment with azathioprine (2 mg/kg/day) or to continue cyclophosphamide therapy at a lower dose (1.5 mg/kg/day). Both treatment groups continued to receive prednisolone 10 mg daily. At 12 months after study entry, both groups received azathioprine at a dose of 1.5 mg/kg/day and prednisolone 7.5 mg daily. The primary end point was relapse, either major (threatened function of the kidney, lung, brain, eye, motor nerve or gut) or minor (affecting at least three

Of the initial 155 subjects, clinical remission was achieved in 93% overall, with 77% reaching this target by 3 months and 16% between 3 and 6 months. These patients were randomly assigned to cyclophosphamide (73 patients) or azathioprine (71 patients). Azathioprine was demonstrated to be equivalent to cyclophosphamide for maintenance therapy. Sixteen percent in the azathioprine group had relapses, compared to 14% in the cyclophosphamide group (p=0.65). Five patients in each group had a major relapse. The most frequent adverse event was neutropenia (55% of patients, including the remission and maintenance phase), with 52% of infections occurring during an episode of neutropenia. There was no difference in renal

A prospective, open-label, multicenter trial, comparing methotrexate and azathioprine for maintenance of remission in GPA and MPA (WEGENT) was designed to detect treatment tolerance [43]. Three-quarters of the patients had GPA. Sixty-three patients who had achieved remission with intravenous cyclophosphamide and corticosteroids received oral azathioprine (2 mg/kg/day) and 63 received methotrexate (initial 0.3 mg/kg/week, progressively increased to 25 mg per week) for 12 months. At the end of the scheduled maintenance therapy period,

outcomes between the groups, with renal failure occurring in only 3% of patients.

other items in the Birmingham Vasculitis Activity Score (BVAS)) [42].

At 6 months, 90% of subjects randomized to methotrexate and 94% of subjects random‐ ized to cyclophosphamide achieved remission (p=0.041). The median time to remission was 3 months (range 1–9) in the methotrexate group and 2 months (range 1–5) in the cyclophos‐ phamide group (p=0.19 log rank test). Of the subjects who achieved remission during the treatment period, 70% of the subjects randomized to methotrexate and 47% of subjects randomized to cyclophosphamide had a relapse, with the time to relapse being significant‐ ly longer in the cyclophosphamide group (median 15 months, range 4-17) compared to the methotrexate group (median 13 months, range 2-17) (P =0.023 log rank test). Leukopenia was more common in the cyclophosphamide group and liver dysfunction was more common in the methotrexate group.

The long term follow-up of patients treated in the NORAM study was recently reported [39]. Data was obtained on all 95 original subjects with a median duration of follow-up of 6 years. Subjects in the methotrexate group required a longer duration of corticosteroid therapy during the trial period of 18 months (median 15 months, interquartile range (IQR) 12-18) compared to 12 months (IQR 12-15) in the cyclophosphamide group, p=0.005). During subsequent followup, the median duration of corticosteroid therapy during months 19-60 was 3.0 years in the methotrexate group and only 1.5 years in the cyclophosphamide group (p=0.004). After the trial period of 18 months, patients' treatment was left at the discretion of their physicians. Physicians were asked to provide information regarding drugs used to manage disease flare such as cyclophosphamide, methotrexate, azathioprine and mycophenolate mofetil. Exposure to cyclophosphamide and these other agents was also longer in the methotrexate group (p=0.037; and p=0.031, respectively).

Overall, the cumulative relapse-free survival from the time of first remission was 69% after 1 year, 32% after 3 years, and 24% after 5 years of follow-up, demonstrating a trend to being higher in the cyclophosphamide group (p=0.056, logrank test). The cumulative overall survival did not differ between treatment arms (p=0.88, log-rank test) and was 98% after 1 year, 93% after 3 years, and 89% after 5 years. The number of serious infections did not differ between treatment groups. The authors have concluded that methotrexate therapy was associated with less effective long-term disease control as compared to cyclophosphamide.
