Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians

Abstract

The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1-2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.

Keywords: IL-1β-inhibition; canakinumab; cryopyrin-associated periodic syndrome (CAPS).

Figure 1.

The clinical spectrum of cryopyrin-associated periodic syndrome (CAPS).

Figure 2.

(a) Daily symptoms of cryopyrin-associated periodic syndrome (CAPS). (b) Urticaria-like rash in a patient with familial cold auto-inflammatory syndrome (FCAS). (c) Conjunctivitis in a patient with Muckle–Wells syndrome (MWS).

Figure 3.

(a) Long-term sequelae of cryopyrin-associated periodic syndrome (CAPS). (b) Growth deficit and bone deformities in a child with neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. (c) Enlarged cerebral ventricles due to persistently increased intracranial pressure. (Figures 3(b) and (c) courtesy of Raphaela Goldbach-Mansky.)

Figure 4.

Interleukin (IL)-1β signal transduction and mechanism of IL-1β inhibition by the specific IL-1β-antibody canakinumab. [Alten et al. 2008; Lachmann et al. 2008]. IL-1R1, IL-1 receptor, IL-1RAcP, IL-1 receptor accessory protein.

Figure 5.

Study design of phase I/II canakinumab dose titration study [Lachmann et al. 2009b].

Figure 6.

Suppression of inflammatory parameters serum amyloid A (SAA) and C-reactive protein (CRP) during long-term treatment of cryopyrin-associated periodic syndrome (CAPS) [Kuemmerle-Deschner et al. 2011a]. *Assessment only for canakinumab-naïve patients.

Figure 7.

Monitoring auto-inflammatory disease activity in cryopyrin-associated periodic syndrome (CAPS). [Kuemmerle-Deschner et al. 2010; Piram et al. 2011]

Figure 8.

Canakinumab dose adjustment according to clinical disease activity and laboratory parameters.

Figure 9.

Diagnostic therapy attempt with short-acting interleukin (IL)-1 inhibitors in patients with cryopyrin-associated periodic syndrome (CAPS).

Figure 10.

Audiogram of a patient with Muckle–Wells syndrome (MWS); hearing loss is particularly marked in the high frequencies and improved with canakinumab therapy.