Inclusion Criteria:

• - Newly diagnosed or relapsing granulomatosis with polyangiitis according to American College of Rheumatology criteria, EMA classification algorithm and/or the 2012 revised Chapel Hill Consensus Conference definition.

• - Aged 18 years or older.

• - Active clinical manifestations attributable to GPA.

• - An inadequate response to previous standard of care therapy including.

1. Both a combination of glucocorticoids plus cyclophosphamide and a combination of glucocorticoids plus rituximab. 2. Or an inadequate response to a combination of glucocorticoids plus rituximab and a contraindication to cyclophosphamide.

• - An inadequate response to treatment defined as follows: 1.

A progressive disease unresponsive to previous standard of care therapy after 12 weeks of treatment. 2. Or a lack of response, defined as < 50% reduction in the disease activity score, after 12 weeks of treatment. 3. Or a persistent active disease attributable to either a vasculitic or a granulomatous manifestation of GPA that requires the maintenance of corticosteroids ≥ 7.5 mg/day of equivalent prednisone after ≥ 12 weeks of treatment.

• - A stable dose of oral glucocorticoids of ≥ 7.5 mg/day of equivalent prednisone within the 4 weeks before enrollment.

Pulses of methylprednisolone (1 to 3 pulses of 7.5 to 15 mg/kg each; ≤ 1000 mg) are allowed if necessary, according to severity before starting the experimental treatment.

• - A stable dose of conventional disease-modifying anti-rheumatic drugs (cDMARD) within 4 weeks before enrollment if the patient is currently treated with a cDMARD.

• - Patients must have the ability to understand the requirements of the study, provide written informed consent prior to participation in the study (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits) - Patients must have an affiliation with a mode of social security (profit or being entitled)

  Exclusion Criteria:

  - An allergy or hypersensitivity to monoclonal antibodies or either of the study drugs (rituximab, abatacept or tocilizumab) or to their excipients.

• - A previous treatment with a combination of rituximab plus a cDMARD, with abatacept, or with tocilizumab.

• - A contraindication to a combination of rituximab plus a cDMARD, to abatacept, or to tocilizumab (including an ongoing infection; history of recent cancer <5 years before enrollment, except for cured non-melanoma skin cancer); pregnancy; and breastfeeding.

• - Patients with severe vasculitis manifestations that requires plasma exchange therapy including severe renal failure with a creatinine level ≥350 µmol/L or severe alveolar haemorrhage.

• - Patients with vasculitis in remission.

• - Patients with symptoms attributable to chronic and non-active GPA.

• - Patients with severe cardiac failure defined as class IV in New York Heart Association.

• - Patients with acute infections or chronic active infections (including HIV, HBV or HCV) - Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment.

• - Pregnant women and lactation.

All women with childbearing potential are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception from the date of consent through the end of the study, and for women who are taking abatacept through 14 weeks after the last treatment administration, for women who are taking tocilizumab through 3 months after the last treatment administration, for women who are taking rituximab in combination with methotrexate through 6 months after the last treatment administration, for women who are taking rituximab in combination with mycofenolate mofetil or with azathioprine through 3 months after the last treatment administration.

• - Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol.

• - Patients included in other investigational therapeutic study within the previous 3 months.

• - Patients suspected not to be observant to the proposed treatments.

• - Laboratory parameter exclusions.

1. aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) > 5 times upper limit of normal. 2. Platelet count <100.000/mm3. 3. White blood cell count <2000/mm3

Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Combination of glucocorticoids and either cyclophosphamide or rituximab is the standard of care for remission-induction of new-onset organ-threatening or life-threatening GPA. Few patients fail to respond to both cyclophosphamide and rituximab, but it is not uncommon for patients to have persistent disease activity resulting in inability to taper glucocorticoids, which is also considered refractory disease. The current recommendations for patients with GPA refractory to remission-induction therapy are to switch from cyclophosphamide to rituximab or from rituximab to cyclophosphamide. However, there are no recommendations for the management of patients with inadequate response after both treatments. Treatment with a biologic disease-modifying antirheumatic drugs (DMARD) or a combination of rituximab and a cDMARD are potential treatments options but have not been properly evaluated in such cases. Among biologic DMARD that have been evaluated in AAV, some have shown promising results, including tocilizumab and abatacept. Identifying the most promising therapeutic strategy for patients with GPA and inadequate response to standard of care therapy may improve management of GPA.

Arms

Active Comparator: Rituximab + cDMARD

Rituximab will be administered at 375 mg/m²/week for four consecutive weeks. Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52. The choice of the cDMARD will be left to the treating clinician and will include either methotrexate, azathioprine or mycophenolate mofetil, but the choice will be preferably methotrexate. Methotrexate will be administered orally or subcutaneously at 0.3 mg/kg/week, azathioprine orally at 2-3 mg/kg/d and mycophenolate mofetil orally at 2-3 g/d.

Experimental: Tocilizumab

Tocilizumab will be administered subcutaneously every week at a fixed dose of 162 mg per week.

Experimental: Abatacept

Abatacept will be administered subcutaneously every week at a fixed dose of 125 mg per week.

Interventions

Drug: - Rituximab

375 mg/m²/week for four consecutive weeks (Week 0, 1, 2 and 3) Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52.

Drug: - Tocilizumab

Subcutaneous injection of 162 mg per week

Drug: - Abatacept

Subcutaneous injection of 125 mg per week