**4. Treatment of granulomatosis with polyangiitis**

The choice of treatments in GPA depends on several forms of the disease (limited vs. diffuse), patient's age, his overall physiological state and in particular his renal function. At present, the choice of treatment according to the immunological profile (ANCA-PR3, ANCA-MPO or ANCA-negative) remains a subject of controversy [22]**.**

#### **4.1 Remission induction therapy**

Regardless the clinical form of GPA, the treatment is based on a combination of corticosteroids with immunosuppressant drug or rituximab. Corticosteroids are used at a dose of 1 mg/kg/day, preceded by methylprednisolone pulses (7.5 to 15 mg/kg/ day) in severe or active cases. The choice of the immunosuppressant drug depends on the clinical form and extent of the disease [22, 23]**.**

#### **4.2 Non-severe or limited forms of granulomatosis with polyangiitis**

Methotrexate, rituximab and cyclophosphamide are effective at inducing remission the limited form of GPA. Although, methotrexate is currently recommended in this patient group [24]**.** The weekly dose is 0.3 mg/kg. According to the NORAM study, its efficacy is comparable to that of cyclophosphamide with a lower risk of infection. Also, mycophenolate mofetil (MMF) is effective as an induction therapy for the limited form of GPA with satisfactory results. Rituximab may be used for patients with recurrent relapses while receiving methotrexate or concerns regarding compliance [24]**.**

### **4.3 Severe or diffuse forms of granulomatosis with polyangiitis**

Both rituximab and cyclophosphamide, in combination with glucocorticoids, have been used for remission induction in GPA [24]**.** Corticosteroids with cyclophosphamide have always represented the gold standard in the treatment of diffuse forms of GPA. Cyclophosphamide can be administrated per os (2mg/kg/day) or by intravenous pulses (15mg/kgevery 2 weeks for the first 3 pulses then every 3 weeks ) for an initial duration of 3 to 6 months. According to the studies, they have comparable results in terms of efficiency and average survival. However, due to the high cumulative dose of the oral route, this modality is associated with a high risk of infectious

events [25, 26]**.** Rituximab or anti-CD20 is now preferred over cyclophosphamide for many reasons. Its efficiency in inducing remission has been proven by numerous studies, especially for relapsed diffuse forms [22, 27, 28]. It is a better-tolerated treatment and is considered less toxic than cyclophosphamide. It has lower risks of malignancy and/or infertility. Also, the risk of infectious complications is almost the same between these two drugs [29]. Rituximab has been approved for use in GPA as a weekly infusion of 375 mg/m2 for 4 consecutive weeks or as two 1-gram infusions spaced two weeks apart. Currently, it is prescribed for relapsed patients, those of childbearing age and/or those who have already received high cumulative doses of cyclophosphamide. A duration of 3 months may be required to achieve maximum therapeutic benefit.

As in all AAVs and by extrapolation to their efficiency in Goodpasture's syndrome, plasma exchange is indicated in severe forms of GPA with alveolar hemorrhage and/or glomerulonephritis. The MEPEX study showed their efficacy in patients with severe renal impairment (creatinine level over 500 umol/l), but this action is not maintained over the long term [30]. The benefit was most pronounced in patients with the highest risk of end-stage renal disease [24]. Polyvalent immunoglobulins are recommended for relapsing or severe disease. The total dose of infusions is 2 g/kg over 2 or 5 days.

#### **4.4 Remission maintenance therapy**

To reduce its iatrogenicity, gradual tapering of corticosteroids is preferable after inducing remission.

• Remission maintenance treatments for non-severe or limited forms of GPA are based on the same immunosuppressant used in the induction phase (methotrexate, MMF) [22]. Methotrexate should be taken for a long-term period (several years). According to the NORAM study, stopping methotrexate at one year of progression increases the risk of relapse of GPA [23]**.** For diffuse forms of GPA, methotrexate and azathioprine represented the conventional remission maintenance drugs in the last years. The WEGENT study concluded that they have comparable results in terms of efficiency, safety and relapse frequency [31]. Rituximab is mentioned in the latest European EULAR/ERA-EDTA guidelines as a remission maintenance drug. Several prospective and retrospective studies have compared rituximab with other molecules such as azathioprine. The results of these studies were in favor of a greater reduction in the relapse rate of GPA by rituximab [22]**.** Therefore, rituximab is now favored and highly recommended over methotrexate or azathioprine for maintaining remission of severe GPA, but cost and other factors may limit rituximab use [24]. Upon remission of GPA, this biomedicine is started within 1 month of the last cyclophosphamide infusion or 4 to 6 months after the start of rituximab induction therapy. It is administered in 5 infusions of 500 mg over 18 months (at D1 and D15 then every 6 months for 18 months) (FDA-approved) [22]**.**
