Schnitzler syndrome:

Schnitzler syndrome is a rare disabling autoinflammatory syndrome characterized by a chronic urticarial rash and monoclonal gammopathy, accompanied by intermittent fever, arthralgia or arthritis or bone pain. Diagnostic criteria have been established. The disease never remits spontaneously. Although there is no standard of care, there have been promising developments in therapeutic options, especially anti-interleukin-1 therapy. Anakinra, a synthetic analogue of the endogenous interleukin-1 receptor antagonist, has caused rapid clinical remission in 24 patients with Schnitzler syndrome. However, to sustain remission, continuous daily administration (100 mg sc) is required. The level of monoclonal protein does not decrease. Side effects of anakinra include painful injection site reactions and neutropenia.

Interleukin-1 and the autoinflammatory diseases:

As a key proinflammatory cytokine mediating local and systemic responses to infection and tissue injury, interleukin-1 can induce a range of responses, including fever, pain sensitization, bone and cartilage destruction, and the acute-phase inflammatory response. The so-called autoinflammatory diseases are mediated entirely by interleukin-1; reducing interleukin-1 activity brings about a rapid and sustained remission. Autoinflammatory diseases include relatively uncommon disorders such as familial Mediterranean fever, adult and juvenile Still's disease, the hyper-IG D syndrome, Behçet's syndrome, the cryoporin-associated periodic syndrome (CAPS), deficiency of the interleukin-1 receptor antagonist (DIRA) and Schnitzler's syndrome. Some common conditions such as gout and type 2 diabetes, are also likely to be autoinflammatory diseases.

Canakinumab:

Canakinumab (Ilaris, Novartis Pharma) is a fully human anti-interleukin-1-bèta monoclonal antibody. Treatment with subcutaneous canakinumab (150 mg) once every 8 weeks was associated with a rapid remission of symptoms in the great majority of children and adults with CAPS. Serum inflammatory markers quickly returned to normal. In general, the side effects seen in this small study (35 patients) were not serious, though suspected infections ware significantly more prevalent in patients receiving canakinumab than in those receiving placebo. The prolonged duration of action of canakinumab and low incidence of injection-site reactions may confer certain advantages over other interleukin-1 inhibitors (anakinra and rilonacept), since both are frequently associated with injection-site reactions, and both require more frequent administration (daily for anakinra and weekly for rilonacept).

Canakinumab was approved for the treatment of CAPS by the US Food and Drug Administration in June 2009 and by the European Medicines Agency in October 2009.

Canakinumab is currently being evaluated for its potential in the treatment of systemic-onset juvenile idiopathic arthritis, diabetes mellitus, and difficult-to-treat gouty arthritis.

Description of the study:

Objectives:

• Primary objective: To evaluate if canakinumab 150mg every 8 weeks can induce and maintain clinical remission in patients with the Schnitzler syndrome.

• Secondary objectives:

  • To test if canakinumab 150mg can induce a complete clinical response at Day 7.
  • To assess if addition canakinumab 150mg given at Day 7 for patients demonstrating only a partial response can induce a complete clinical response at Day 14.
  • To evaluate if canakinumab 300mg every 8 weeks can maintain clinical remission in those patients who required canakinumab 150 mg additional dose on Day 7 and achieved clinical remission at Day 14.
  • To evaluate the safety of canakinumab treatment in patients with the Schnitzler syndrome.
  • To assess the changes in C-reactive protein (CRP) levels during the treatment period.

Study rationale:

Although no standard therapy has been established for the Schnitzler syndrome, given the rarity of this auto-inflammatory syndrome, reports on the use of Anakinra, a synthetic analog of the endogenous interleukin-1 receptor antagonist, have been encouraging. However, side effects (including local infusion site reactions and neutropenia) and the need for daily sc administration have hampered its use. The anti-interleukin-1-inhibitor canakinumab may constitute an effective and more convenient alternative.

Inclusion Criteria:

• Patients with active Schnitzler syndrome after withdrawal of anakinra or tapering of corticosteroids.
• Male and female patients at least 18 years of age at the time of screening visit.
• Signed patient informed consent
• Negative QuantiFERON test or negative Purified Protein Derivative (PPD) test (<5 mm induration) at screening or within 1 month prior to the screening visit, according to Belgium guidelines. Patients with a positive PPD test (=5 mm induration) at screeninig may be enrolled only if they have a negative chest x-ray or negative QuantiFERON test (QFT-TB G In-Tube).
• Adequate contraception in females of childbearing potential.

Exclusion Criteria:

• Pregnant or nursing (lactating) women
• History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot)
• Serologic evidence of active hepatitis B or C infection
• Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose.
• History of significant medical conditions, which in the investigator's opinion would exclude the patient from participating in this trial.
• History of recurrent and/or evidence of active bacterial, fungal or viral infection(s).