Tocilizumab in Chronic Inflammatory CPPD Disease

Calcium pyrophosphate deposition (CPPD) disease affects 4 to 7% of the adult population. CPP crystals are responsible for inflammatory flares affecting one or more joints. The inflammation triggered by CPP crystals resembles that associated with sodium urate crystals in gout and depends on inflammatory cytokines such as interleukins (IL-) 1β and -6. The usual treatments are those used in gout flares (colchicine, NSAIDs, corticosteroids, IL-1β inhibitors), and most often control monoarticular involvement. The chronic inflammatory polyarticular form, on the other hand, is more difficult to treat, causing significant pain and disability, as well as joint destruction. In refractory forms, or in cases of intolerance to standard treatments, alternative therapies are required. In this context, the investigators treated 11 patients with refractory chronic inflammatory CPPD with tocilizumab (TCZ), an anti-IL-6 receptor (IL-6R) monoclonal antibody. After 3 monthly infusions, improvement was estimated at over 75% (PMID 2213498). Our hypothesis is that inhibiting IL-6 is an effective therapeutic option in chronic inflammatory CPPD refractory to conventional therapies.

Main objective and primary endpoint:

• To demonstrate the efficacy of IL-6 inhibition in treatment-refractory chronic inflammatory forms of CPPD disease.
• Our endpoint will be the change in global pain VAS between initiation and M4, i.e. one month after the 3rd infusion. VAS will be assessed after 24 hours off analgesics.

Secondary objectives and endpoints:

• Efficacy: DAS44, number of swollen, painful joints, overall disease activity VAS, fatigue VAS; overall effect on pain: area under the VAS curve (AUC); proportion of patients responding from M2 to M6 (improvement ≥ 50% of initial pain VAS) and complete response (improvement ≥ 80% of initial pain VAS); relapse rate; improvement in quality of life (SF-36, HAQ, EQ-5D-3L questionnaires)
• Tolerance: infusion reactions, infections, neutropenia, hepatic cytolysis, lipid profile

This is a phase III, multicentre, randomized, controlled, double-blind, superiority study, including 2 parallel groups with a 1:1 distribution. This trial will involve adults suffering from the chronic inflammatory polyarticular form of CPPD disease.

This study will involve 80 participants recruited in 12 centres in France.

Inclusion criteria

• Adults > 18 years
• Diagnosis of CPPD according to ACR/EULAR 2023 classification criteria
• Persistent inflammatory pain (> 3 months) or ≥ 2 arthritics/month
• Number of painful joints (NAD) > 3
• Overall pain VAS (0_100) > 40 mm
• Failure, intolerance or impossibility of repeated use of usual treatments: colchicine, NSAIDs, corticosteroids and anakinra
• Use of an effective method of contraception in women of childbearing age until 3 months after the end of the study.
• Informed consent

Exclusion criteria

• Presence of anti-CPP antibodies > 50 IU/ml
• Recurrent or chronic infections
• History of severe infection (= requiring hospitalization)
• Active infection
• Vaccination with live or attenuated vaccine within 4 weeks prior to inclusion
• History of intestinal ulceration or diverticulitis Untreated latent tuberculosis
• History of viral hepatitis B ou C
• Symptoms suggestive of demyelinating disease of the central nervous system
• History of cancer, active cancer, or suspected cancer
• Neutropenia < 2000 elements/mm3, thrombocytopenia < 100 000/mm3
• Elevated transaminases > 3 x ULN
• Known hypersensitivity to the active substance or one of the excipients;
• Known severe immune deficiency
• Patients not meeting classification criteria
• Concomitant treatment with biological or targeted therapies, or immunosuppressive therapy (including methotrexate, leflunomide, azathioprine), systemic corticosteroids, anakinra, IL-6 inhibitors in subcutaneous injection, anti-TNF agents, and JAK. If these treatments are used before inclusion, a washout period corresponding to at least five times their respective mean terminal half-life must be respected.
• inhibitors.
• Previous treatment with tocilizumab
• Concomitant treatment with methylprednisolone, dexamethasone, atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, cyclosporine or benzodiazepines
• Dyslipidemia, hypertension or poorly controlled cardiovascular disease
• Scheduled surgery
• Difficulty to understand French, illiteracy
• Pregnant women, women in labor or nursing mothers
• Persons deprived of their liberty, adults under legal protection or unable to express their consent
• Persons not affiliated to a social security scheme or beneficiaries of such a scheme
• Participation in another interventional study