MEthotrexate Versus TOcilizumab for Treatment of GIant Cell Arteritis: a Multicenter, Randomized, Controlled Trial

Inclusion criteria

• Written consent
• Affiliation to a social security system
• Diagnosis of GCA, as defined by the revised GCA diagnosis criteria:44

• Age ≥50 years at disease onset
• AND History of erythrocyte sedimentation rate (ESR) ≥50 mm/h OR CRP≥20 mg/L (not mandatory if TAB is positive: see below)
• AND At least one of the following:
• unequivocal cranial symptoms of GCA (new onset headache, scalp tenderness, jaw claudication, temporal artery abnormality, ischemia-related vision loss)
• unequivocal symptoms of polymyalgia rheumatica (PMR)

o AND At least one of the following:

• Temporal artery biopsy (TAB) compatible with the diagnosis of GCA (non-necrotizing vasculitis with a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells)
• Evidence of large vessel vasculitis (aorta and/or epiaortic arteries):

• angio-CT or angio-MRI: thickened arterial wall (≥2mm for the aorta and ≥1mm for epiaortic arteries) and/or contrast-enhanced arteries in T1-weighted sequences
• PET scan: grade 3 tracer uptake of the arterial wall (grade 3 = arterial SUVmax superior to the SUVmax of the liver)
• Active GCA within 6 weeks before randomization. Active GCA is defined by ESR ≥30 mm/h or CRP ≥10 mg/L and at least one of the following:

• ≥1 unequivocal cranial symptom(s) of GCA (new onset localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or otherwise unexplained mouth or jaw pain upon mastication)
• ≥1 unequivocal symptom(s) of PMR, defined as shoulder and/or hip girdle pain associated with inflammatory stiffness
• any other feature(s) judged by the clinical investigator to be consistent with GCA or PMR flares

Exclusion criteria

• Uncontrolled psychotic state
• Patient unable to give his/her consent
• Premenopausal women (menopause is defined as amenorrhea for more than 12 consecutive months)
• Non-compliant patients
• Weight<40 Kg or >100Kg
• Patients under maintenance of justice, wardship or legal guardianship
• History of intoxication (alcohol or medication) requiring hospitalization within 12 months before inclusion
• Current chronic alcohol abuse (consumption > 20g/day)
• Recent or incoming surgery within 12 months after inclusion
• History of stem cell or organ transplantation (except corneas performed more than 3 months prior inclusion)
• Primary or secondary immunodeficiency
• Hypersensitivity to methotrexate or tocilizumab, one of its excipients or another human or murine monoclonal antibody
• History of diverticulitis, inflammatory bowel disease, or other symptomatic gastrointestinal tract condition that might predispose to bowel perforation
• Patient refusing to sign methotrexate safety contract
• Prior treatment with any of the following:

• Tocilizumab or methotrexate within 12 weeks before inclusion
• Treatment with rituximab or other anti-CD20 agent within one year before inclusion
• Treatment with cyclophosphamide within one year before inclusion
• Hydroxychloroquine, cyclosporine A, dapsone, azathioprine, mycophenolate mofetil or janus kinase inhibitors within 4 weeks before inclusion
• Tumor necrosis factor inhibitors within 8 weeks (infliximab) or 2 weeks (adalimumab or etanercept) before inclusion
• Anakinra within 1 week before inclusion
• Long-term systemic glucocorticoid therapy ((except dermocorticoids and inhaled corticoids) for other conditions than GCA or PMR
• Patient with ≥3 prior glucocorticoid systematic therapies for another disease than GCA or PMR within the 6 months before inclusion
• Long-term treatment with sulfamethoxazole/trimethoprim (Bactrim®)
• Live vaccine administered within 30 days before inclusion
• Laboratory abnormalities:

• AST or ALT >1.5 x upper limit of normal (ULN)
• total bilirubin >ULN
• platelets<100 G/L
• leukocytes <3 G/L
• neutropenia <1.5 G/L
• lymphopenia <0.5 G/L
• haemoglobin <8 g/dL (not related to GCA activity)
• clearance of creatinine <30 ml/min/1,73 m2 [CKD EPI 2009]
• positive HBs antigen or positive HCV antibodies
• Infections:

• History of viral hepatitis B or C (chronic or acute)
• HIV infection
• Persistent infection or severe infection requiring hospitalization or intravenous antibiotics within 30 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)
• Proven infection requiring oral antibiotics within 14 days before inclusion (antibiotic treatment tests are allowed, regardless of duration and route of administration)
• Prior history of histoplasmosis or listeriosis
• Active tuberculosis
• Latent tuberculosis (diagnosis based on history of non-treated contact, opacity with a diameter greater than 1 cm on chest radiography, or positive in vitro test: Quantiferon Gold® or T-Spot-TB®).

NB: a history of tuberculosis for which treatment is over and was correctly precribed regarding usual recommendations is not an exclusion criteria, whatever the results of Quantiferon Gold® or T-Spot-TB® tests.

• Unstable or poorly controlled, acute or chronic disease, not due to GCA, and which contraindicates tocilizumab or methotrexate:

• Recurrent infections, unstable ischemic heart disease, renal failure (creatinine clearance <30 ml/min/1,73 m2 [CKD EPI 2009]), liver failure, current liver disease, heart failure ≥ NYHA stage III/IV, respiratory failure
• Neoplasia < 5 years, (except for in situ cervical cancer and skin carcinoma, except melanoma, with R0 resection)