Cryopyrin-associated Periodic Syndromes – Patient Quality of Life and Psychological Impact

Cryopyrin-associated periodic syndromes (CAPS), also known as cryopyrinopathies, encompass a spectrum of dominantly inherited debilitating diseases that increase in severity from familial cold autoinflammatory syndrome (FCAS) and familial cold urticaria (FCU) to Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID).^1,2 Their common features include chronic urticaria (cold-induced in FCU), evening and/or nocturnal chills, fevers and conjunctivitis. CAPS also cause mild to severe constitutional symptoms, such as fatigue, headaches, arthralgia/myalgia (often exacerbated by exercise, diffuse pain, cognitive and developmental impairment and, occasionally, psychiatric disturbances. The main symptoms of CAPS are summarised in Figure 1. Patients with MWS usually develop sensory deafness during the second decade of life and may also develop secondary amyloidosis in 30% of cases. In addition to these findings, patients with CINCA/NOMID can present with facial dysmorphism, chronic intracranial hypertension, aseptic meningitis and epiphyseal overgrowth of the long bones.

For many years CAPS symptoms were poorly recognised and the treatment was only supportive. Patients were given non-steroidal antiinflammatory drugs (NSAIDs), paracetamol and oral steroids, without satisfactory results. For this reason, many patients were discouraged from continuing to make regular visits to their family (or specialist) physician. They also had limited social fulfilment.

Recently, the molecular mechanisms of these disorders have become better understood. Inherited or de novo mutation of the cryopyrin gene modifies the function (gain of function) of the inflammasome. ³ This is a multimolecular complex located inside the leukocytes that senses exogenous particles (such as bacterial debris and urate crystals) inside the cytoplasm.³ One main consequence is an excessive production of interleukin-1 beta (IL-1β), a potent proinflammatory cytokine. Physical consequences of deregulated IL-1β secretion include fever, severe fatigue, decreased pain threshold and increased bone resorption.⁴ In addition, IL-1β induces liver secretion of acute-phase reactants, such as C-reactive protein (CRP) and serum amyloid-associated protein (SAA).

Novel therapies targeting IL-1β are now available to CAPS patients. Anakinra (Kineret®) is an IL-1Ra agonist that specifically inhibits the IL-1 receptor and targets both IL-1α and IL-1β. Small uncontrolled studies have shown that daily injections of anakinra produce dramatic effects on CAPS symptoms and normalise serum levels of both CRP and SAA. ^5,6 However, anakinra is not licensed for the treatment of CAPS and due to the requirement for daily injections it is often poorly tolerated by patients. A placebo-controlled study using rilonacept (Arcalyst®), a soluble receptor targeting IL-1α and IL-1β and also blocking endogenous IL-1Ra, produced significant results in patients with FCAS who received once-weekly injections.⁷ This drug is now licensed in the US for the FCAS and MWS forms of CAPS in patients over 12 years of age. Finally, canakinumab (Ilaris®), a fully human monoclonal antibody that selectively targets IL-1β, has demonstrated long-lasting remission in patients with only a single injection every eight weeks, in both children and adults, with all CAPS phenotypes. ⁸ Canakinumab has recently been approved for patients with CAPS as young as four years of age in the US (excluding NOMID) and in Switzerland. As therapeutic trials were ongoing with these new, effective drugs, physicians and patients themselves realised how much CAPS symptoms affected quality of life. Moreover, the requirement for appropriate instruments to measure disease activity, response to treatment and quality of life became evident.