Study of Salvage Therapy to Treat Patients with Granulomatosis with Polyangiitis

Inclusion Criteria:

• Newly diagnosed or relapsing granulomatosis with polyangiitis according to AmericanCollege of Rheumatology criteria, EMA classification algorithm and/or the 2012revised 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 either :

1. A combination of glucocorticoids plus cyclophosphamide

2. AND /OR a combination of glucocorticoids plus rituximab

• 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 activityscore, after 12 weeks of treatment

3. Or a persistent active disease attributable to either a vasculitic or agranulomatous manifestation of GPA that requires the maintenance ofcorticosteroids ≥ 7.5 mg/day of equivalent prednisone after ≥ 12 weeks oftreatment.

• A stable dose of oral glucocorticoids of ≥ 7.5 mg/day of equivalent prednisonewithin 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 severitybefore 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, providewritten informed consent prior to participation in the study (including consent forthe use and disclosure of research-related health information) and comply with thestudy protocol procedures (including required study visits)

• Patients must have an affiliation with a mode of social security (profit or beingentitled)

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, withtofacitinib, or with tocilizumab

• A contraindication to a combination of rituximab plus a cDMARD, to tofacitinib, orto tocilizumab (including an ongoing infection; history of recent cancer <5 yearsbefore enrollment, except for cured non-melanoma skin cancer); pregnancy; andbreastfeeding.

• Patients with severe vasculitis manifestations that requires plasma exchange therapyincluding severe renal failure with a creatinine level ≥350 µmol/L or severealveolar 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 HeartAssociation

• Patients with acute infections or chronic active infections (including HIV, HBV orHCV)

• Patients with active cancer or recent cancer (<5 years), except basocellularcarcinoma and prostatic cancer of low activity controlled by hormonal treatment

• Pregnant women and lactation. All women with childbearing potential are required tohave a negative serum pregnancy test before treatment and must agree to maintainhighly effective contraception from the date of consent through the end of thestudy, and for women who are taking tocilizumab or tofacitinib through 3 monthsafter the last treatment administration, for women who are taking rituximab incombination with methotrexate through 6 months after the last treatmentadministration, for women who are taking rituximab in combination with mycofenolatemofetil or with azathioprine through 3 months after the last treatmentadministration

• Patients with other uncontrolled diseases, including drug or alcohol abuse, severepsychiatric diseases, that could interfere with participation in the trial accordingto the protocol

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

• 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 upperlimit of normal

2. Platelet count <100.000/mm3

3. White blood cell count <2000/mm3