**9. Treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)**

Most of the studies in AAV include only a small number of patients with EGPA or exclude them altogether. We will discuss trials performed specifically in EGPA.

#### **9.1. EGPA with poor prognosis**

40, 40 and 40 mg, for a total dose of 134 mg. CAMPATH-1H was readministered for relapsing disease if the initial treatment was tolerated. A total of 71 patients were treated and followed for a mean of 5 years. Sixty-five percent of patients achieved clinical remission, and an additional 20% had a clinically significant improvement in disease activity but still required greater than 10 mg of prednisolone per day or an additional immunosuppressive agent to control disease activity. Almost all subjects relapsed after 9 months, with better renal function and the absence of neurologic involvement protective for relapse. Unfortunately, 44% of the cohort died during the follow-up period, 5 patients were diagnosed with malignancy, and 11% developed Graves disease. These adverse events may limit the use of alemtuzumab in practice

The SOLUTION protocol was an uncontrolled prospective open-label study of ATG in 15 subjects with refractory GPA [71]. ATG was given intravenously at a dose of 2.5 mg/kg for a mean of 2 doses. The authors describe partial remission in 9/15 subjects and complete remission in 4/15 with reduced prednisone requirements (mean 49 mg/day to 13 mg/day) and only experiencing relapse after 8 months. However, 2 patients died and 5 others developed severe

There have been case reports and case series of patients with AAV limited to the upper and/or lower respiratory tract treated with T/S for induction of remission with a good outcome [72]. A study of 72patients withGPAlookedatthe role ofT/S forinductionofremissioninthe localized stage, and maintenance of remission in the generalized stage [73]. Nineteen patients with localized disease received T/S (2×960 mg/day) with 58% achieving complete or partial remis‐ sion for a median of 43 months. Patients with generalized disease in remission did poorly with T/S, with 42% of those treated with T/S alone relapsing after a median of 13 months compared

T/S was found to be superior to placebo in maintaining remission in a prospective, placebo controlled study of 81 patients with GPA, 41 of whom received T/S after induction of remission of generalized disease [74]. At 24 months of follow-up 82% of patients in the T/S group were still in remission, as compared to only 60% in the placebo group, with a relative risk of relapse of 0.40 (95%CI 0.17 to 0.98). This reduction was especially evident with respect to relapses

Therefore, T/S can be considered for the induction of remission of localized GPA but patients should be monitored carefully for signs of progression to systemic disease. The efficacy of maintenance of remission in generalized disease is controversial and currently not the

to a relapse rate of 29% at a median of 23 months in the patients not receiving T/S.

to highly selected patients or those with disease refractory to all other agents.

**7.6. Antithymocyte globulin (ATG)**

206 Updates in the Diagnosis and Treatment of Vasculitis

**8. Treatment of localized vasculitis**

**8.1. Trimethoprim/sulfamethoxazole (T/S)**

involving the upper airways.

recommended standard of practice.

infections.

A prospective, multicenter, randomized trial of patients newly diagnosed with EGPA and at least 1 poor prognosis factor (creatinine >140 μmol/l (1.58 mg/dl); proteinuria >1 gm/ day; or central nervous system, gastrointestinal, or myocardial involvement) was conduct‐ ed to determine the shortest immunosuppressant duration able to limit the occurrence of side effects and still induce and maintain disease remission by comparing glucocorticoids and 6 compared to 12 intravenous cyclophosphamide pulses [75]. All patients received 3 consecutive intravenous pulses of methylprednisolone (15 mg/kg) followed by oral prednisone (1 mg/kg/day) for 3 weeks followed by a tapering regime. Intravenous cyclophosphamide (0.6 g/m2 ) was given every 2 weeks for 1 month, then every 4 weeks, and patients were randomized to receive either 6 or 12 cyclophosphamide pulses. The cumulative cyclophosphamide dose was twice as high in the 12-pulse group than in the 6-pulse group (6.6 g/m2 versus 3.48 g/m2 ). There was a non-significant difference in the proportion of patients achieving complete remission, at 91% for the group receiving 6 pulses and 84% for the group receiving 12 pulses. Relapse frequency demonstrated a trend to significance at 74% for the group receiving 6-pulses compared to 62% in the 12-pulse group (p=0.07), and the mean time to first relapse was 268 days in the 12-pulse group compared to 222 days in the 6-pulse group, although this was not statistically different. Adverse events and deaths were equal between both groups.

#### **9.2. EGPA without poor prognosis factor**

One study examined treatment efficacy of corticosteroids as first-line treatment of EGPA without poor prognosis factors, and the use of azathioprine compared to intravenous cyclophosphamide for treatment failure or relapse [76]. Subjects could receive 1 intrave‐ nous pulse of methylprednisolone (15 mg/kg) and then oral prednisone (1 mg/kg/day for 3 weeks) followed by a tapering regimen. If the prednisone could not be tapered below 20 mg, or if the patient experienced a relapse, they were randomized to azathioprine (2 mg/kg/day for 6 months) or 6 cyclophosphamide doses (0.6 g/m2 every 2 weeks for 1 month, then every 4 weeks). Ninety-three percent of subjects achieved remission, with a 1 year survival rate of 100% and 5 year survival rate of 97%. Of the subjects achieving remission, 37% relapsed, and 3% could not reduce their prednisone. A total of 19 sub‐ jects went onto randomization with 10 receiving cyclophosphamide and 9 receiving azathioprine. Fifty percent of the cyclophosphamide subjects achieved remission, com‐ pared to 78% of the azathioprine subjects. Low-dose corticosteroid therapy was required in 79% of subjects long-term, primarily due to lung disease.

#### **10. Chapter summary**

The treatment of AAV is directed at achieving disease control to prevent morbidity and mortality, while minimizing treatment toxicity. Corticosteroid use remains critical in rapidly achieving disease activity suppression, whereas cyclophosphamide and rituximab regimens should be reserved for induction of severe generalized disease, and plasma exchange for severe renal disease. In less severe cases of systemic disease methotrexate is suitable for remission induction. Maintenance of remission is achieved preferably with azathioprine or methotrexate, with leflunomide, mycophenolate mofetil and cyclophosphamide remaining as options. Finally, new discoveries and research will certify the role of alternative agents, such as monoclonal anti-tumor necrosis factor therapy, IVIg, DSG, ATG and CAMPATH-1, in refractory disease.

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