**6. Maintenance of remission**

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 for maintenance of remission.

#### **6.1. Azathioprine**

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60 years of age, and the drug was withdrawn if the total white

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

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

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

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.

/liter. At remission, cyclophosphamide was reduced to

blood cell count fell below 4 x109

198 Updates in the Diagnosis and Treatment of Vasculitis

received no immunosuppressant agents.

common in the methotrexate group.

(p=0.037; and p=0.031, respectively).

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

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

#### **6.2. Methotrexate**

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, azathioprine and methotrexate were withdrawn over a period of 3 months at the discretion of the treating physician. T/S was recommended for 2 additional years for patients with GPA after discontinuation of the maintenance immunosuppressive agents. The primary end point was an adverse event requiring discontinuation of the study drug or causing death.

choice for maintenance of remission in AAV, but could be used in situations of intolerance or

Treatment of ANCA-Associated Vasculitis in Adults

http://dx.doi.org/10.5772/54290

201

Leflunomide is a disease-modifying agent commonly used in the treatment of rheumatoid arthritis as an alternative to methotrexate. A prospective randomized controlled trial of leflunomide compared to methotrexate in patients with generalized GPA for maintenance of remission was conducted in 5 German rheumatology centres [46]. The study was powered to find equivalence between the 2 drugs. Patients achieving complete or partial remission with daily oral cyclophosphamide (2mg/kg) and prednisolone and maintained remission for at least 3 months were enrolled in the study. Partial remission was defined as partial improvement of the disease persisting for at least 3 months represented by a constant disease extent index and BVAS. Complete remission was defined as the absence of pathological findings in clinical, radiological and serological investigations, irrespective of the ANCA titre. Twenty-eight subjects received oral methotrexate starting at a dose of 7.5 mg/week, increased over 9 weeks to 20 mg/week. Folic acid 10 mg weekly was taken the day after methotrexate. Twenty-six patients received leflunomide with a loading dose of 100 mg daily for 3 days, followed by 20 mg daily and then increased to 30 mg daily after 4 weeks. Prednisone was allowed at a dose of 10mg/day or less, and was tapered by 2.5mg/month in the absence of disease activity until a dose of 5 mg was reached, and then by 1 mg/month thereafter. The primary efficacy outcome

In the leflunomide group, 23% of subjects experienced a relapse, compared to 46% of metho‐ trexate subjects (p=0.09), and the incidence of major relapses was significantly higher in the methotrexate group (p=0.037). The study was terminated prematurely in September 2003 after the advisory board had decided that the high rate of major relapses in the methotrexate group

*Safety*: There was no significant difference in the number of adverse events between the groups. Thirty-four adverse events were observed in the leflunomide group and 17 in the methotrexate group (p=0.09). Leflunomide was stopped in two patients with intractable hypertension, one patient with peripheral neuropathy and one patient with leucopenia, whereas no patient stopped due to adverse events in the methotrexate group. Twenty-five infectious episodes, 13 in the leflunomide group and 12 in the methotrexate group were noted, all responding well to

Some patients have disease that proves to be refractory to the therapies used for induction and maintenance of remission as above. Typically, patients with lung and upper airway involve‐ ment, positive PR3-ANCA and severe renal involvement have more resistant disease [47-49]. Relapse is also frequent in AAV, with an overall risk of 38% at 5 years seen in a large cohort of 535 patients from 70 European trial sites between 1995 and 2002 [32]. The presence of positive

contraindication to azathioprine.

was the number of major and minor relapses.

conventional antibiotic treatment on outpatient basis.

**7. Refractory/relapsing disease**

**6.4. Leflunomide**

was not acceptable.

At the censoring date for analysis, the mean follow-up after randomization was 29 months. Adverse events leading to the primary end point (i.e., discontinuation of the study drug or death) occurred in 11% of the azathioprine group and 19% in the methotrexate group (p=0.21). After starting maintenance therapy, 46% of azathioprine recipients had at least one adverse event as compared with 56% of methotrexate recipients (p= 0.29). Thirty-six percent of azathioprine subjects and 33% of methotrexate subjects had a relapse (p=0.71). In 73% of the patients the relapse occurred after discontinuation of the drugs. This study demonstrated that the two agents were equivalent in safety and also efficacy. There was a trend toward a higher risk of adverse events with methotrexate, with a hazard ratio of 1.65 (95%CI, 0.65-4.18).

#### **6.3. Mycophenolate mofetil**

Mycophenolate mofetil is a prodrug of mycophenolic acid, which is a reversible inhibitor of inosine monophosphate dehydrogenase in guanosine nucleotide synthesis, upon which T and B cells are dependent, and has cytostatic effects on lymphocytes [44]. It has been proposed as a less toxic alternative to azathioprine and has been evaluated in one randomized trial. The IMPROVE study was an open-label trial to assess whether mycophenolate mofetil reduces the risk of relapse compared with azathioprine in patients with AAV in remission [45]. All patients received cyclophosphamide (daily oral or intermittent intravenous doses for a maximum of 6 months) and glucocorticoids (up to 3 g of methylprednisolone over 3 days was allowed for severe disease, then 1 mg/kg/day (maximum 80 mg) of oral prednisolone) for induction of remission. Plasma exchange could also be used for severe disease. Oral steroids were reduced according to a standardized schedule to 15 mg/day at the start of the remission regimen, tapered to 5 mg/day after 12 months, and were withdrawn after 24 months. One hundred and fifty six patients with a new diagnosis of GPA and MPA were enrolled after remission was achieved. The azathioprine group (n=80) initially received 2 mg/kg/day (maximum 200 mg), with dose reductions to 1.5 mg/kg/day after 12 months and 1 mg/kg/day after 18 months, with drug withdrawal after 42 months. Seventy-six patients assigned to the mycophenolate mofetil group received 2 g/day, which was reduced to 1500 mg/day after 12 months, 1000 mg/day after 18 months, and withdrawn after 42 months. The primary end point was relapse-free survival, defined as the time from remission to the first relapse (major or minor), withdrawal, death or loss to follow-up, or the end of the follow-up period.

Median follow-up for both treatment groups from start of maintenance therapy was 39 months. Relapses were more common in the mycophenolate mofetil group. In total, 55% of the mycophenolate mofetil recipients experienced relapses (18 major, 24 minor), as compared to 38% of azathioprine recipients (10 major, 20 minor), with an unadjusted hazard ratio for mycophenolate mofetil use of 1.69 (95%CI, 1.06-2.70; p=0.03) at 4 years. The risk of severe adverse events was not significantly different between groups, with a hazard ratio of 0.53 (95%CI, 0.23-1.18, p=0.12). Therefore mycophenolate mofetil should not be considered as a first choice for maintenance of remission in AAV, but could be used in situations of intolerance or contraindication to azathioprine.

#### **6.4. Leflunomide**

azathioprine and methotrexate were withdrawn over a period of 3 months at the discretion of the treating physician. T/S was recommended for 2 additional years for patients with GPA after discontinuation of the maintenance immunosuppressive agents. The primary end point

At the censoring date for analysis, the mean follow-up after randomization was 29 months. Adverse events leading to the primary end point (i.e., discontinuation of the study drug or death) occurred in 11% of the azathioprine group and 19% in the methotrexate group (p=0.21). After starting maintenance therapy, 46% of azathioprine recipients had at least one adverse event as compared with 56% of methotrexate recipients (p= 0.29). Thirty-six percent of azathioprine subjects and 33% of methotrexate subjects had a relapse (p=0.71). In 73% of the patients the relapse occurred after discontinuation of the drugs. This study demonstrated that the two agents were equivalent in safety and also efficacy. There was a trend toward a higher risk of adverse events with methotrexate, with a hazard ratio of 1.65 (95%CI, 0.65-4.18).

Mycophenolate mofetil is a prodrug of mycophenolic acid, which is a reversible inhibitor of inosine monophosphate dehydrogenase in guanosine nucleotide synthesis, upon which T and B cells are dependent, and has cytostatic effects on lymphocytes [44]. It has been proposed as a less toxic alternative to azathioprine and has been evaluated in one randomized trial. The IMPROVE study was an open-label trial to assess whether mycophenolate mofetil reduces the risk of relapse compared with azathioprine in patients with AAV in remission [45]. All patients received cyclophosphamide (daily oral or intermittent intravenous doses for a maximum of 6 months) and glucocorticoids (up to 3 g of methylprednisolone over 3 days was allowed for severe disease, then 1 mg/kg/day (maximum 80 mg) of oral prednisolone) for induction of remission. Plasma exchange could also be used for severe disease. Oral steroids were reduced according to a standardized schedule to 15 mg/day at the start of the remission regimen, tapered to 5 mg/day after 12 months, and were withdrawn after 24 months. One hundred and fifty six patients with a new diagnosis of GPA and MPA were enrolled after remission was achieved. The azathioprine group (n=80) initially received 2 mg/kg/day (maximum 200 mg), with dose reductions to 1.5 mg/kg/day after 12 months and 1 mg/kg/day after 18 months, with drug withdrawal after 42 months. Seventy-six patients assigned to the mycophenolate mofetil group received 2 g/day, which was reduced to 1500 mg/day after 12 months, 1000 mg/day after 18 months, and withdrawn after 42 months. The primary end point was relapse-free survival, defined as the time from remission to the first relapse (major or minor), withdrawal, death or

Median follow-up for both treatment groups from start of maintenance therapy was 39 months. Relapses were more common in the mycophenolate mofetil group. In total, 55% of the mycophenolate mofetil recipients experienced relapses (18 major, 24 minor), as compared to 38% of azathioprine recipients (10 major, 20 minor), with an unadjusted hazard ratio for mycophenolate mofetil use of 1.69 (95%CI, 1.06-2.70; p=0.03) at 4 years. The risk of severe adverse events was not significantly different between groups, with a hazard ratio of 0.53 (95%CI, 0.23-1.18, p=0.12). Therefore mycophenolate mofetil should not be considered as a first

was an adverse event requiring discontinuation of the study drug or causing death.

**6.3. Mycophenolate mofetil**

200 Updates in the Diagnosis and Treatment of Vasculitis

loss to follow-up, or the end of the follow-up period.

Leflunomide is a disease-modifying agent commonly used in the treatment of rheumatoid arthritis as an alternative to methotrexate. A prospective randomized controlled trial of leflunomide compared to methotrexate in patients with generalized GPA for maintenance of remission was conducted in 5 German rheumatology centres [46]. The study was powered to find equivalence between the 2 drugs. Patients achieving complete or partial remission with daily oral cyclophosphamide (2mg/kg) and prednisolone and maintained remission for at least 3 months were enrolled in the study. Partial remission was defined as partial improvement of the disease persisting for at least 3 months represented by a constant disease extent index and BVAS. Complete remission was defined as the absence of pathological findings in clinical, radiological and serological investigations, irrespective of the ANCA titre. Twenty-eight subjects received oral methotrexate starting at a dose of 7.5 mg/week, increased over 9 weeks to 20 mg/week. Folic acid 10 mg weekly was taken the day after methotrexate. Twenty-six patients received leflunomide with a loading dose of 100 mg daily for 3 days, followed by 20 mg daily and then increased to 30 mg daily after 4 weeks. Prednisone was allowed at a dose of 10mg/day or less, and was tapered by 2.5mg/month in the absence of disease activity until a dose of 5 mg was reached, and then by 1 mg/month thereafter. The primary efficacy outcome was the number of major and minor relapses.

In the leflunomide group, 23% of subjects experienced a relapse, compared to 46% of metho‐ trexate subjects (p=0.09), and the incidence of major relapses was significantly higher in the methotrexate group (p=0.037). The study was terminated prematurely in September 2003 after the advisory board had decided that the high rate of major relapses in the methotrexate group was not acceptable.

*Safety*: There was no significant difference in the number of adverse events between the groups. Thirty-four adverse events were observed in the leflunomide group and 17 in the methotrexate group (p=0.09). Leflunomide was stopped in two patients with intractable hypertension, one patient with peripheral neuropathy and one patient with leucopenia, whereas no patient stopped due to adverse events in the methotrexate group. Twenty-five infectious episodes, 13 in the leflunomide group and 12 in the methotrexate group were noted, all responding well to conventional antibiotic treatment on outpatient basis.
