Management of Cryopyrin-associated Periodic Syndromes

Auto-inflammatory syndromes form a class of inherited diseases that result from dysregulation of innate immunity. Familial cold autoinflammatory syndrome (FCAS; also known as familial cold urticaria), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disorder (NOMID; also known as chronic infantile neurological cutaneous and articular syndrome) are rare disorders within the auto-inflammatory category, with only several hundred documented cases in the US. The protein cryopyrin (Nalp3),¹ which regulates the interleukin-1 (IL-1) pathway,² is coded by the NLRP3 (CIAS1) gene. Aberrant regulation of this pathway caused by mutations in this gene have been associated with excessive inflammation,³ so the terms cryopyrinopathies or cryopyrinassociated periodic syndromes (CAPS) have been created to encompass all three diseases. This article will focus on the pathogenesis of CAPS and inhibitors of IL-1β signalling that have demonstrated efficacy in treating these conditions.

Clinical Features
CAPS constitute a spectrum of disease severity, with FCAS being the mildest condition and NOMID the most severe⁴ (see Figure 1). Patients with CAPS usually present with several shared clinical features, including an urticaria-like rash that appears soon after birth. All patients possess some degree of systemic inflammation in the form of fever and/or chills; in most cases there is some involvement of the joints and eyes. In addition to these common characteristics, there are critical features distinguishing FCAS, MWS and NOMID. Symptoms of FCAS are triggered by cold exposure. The onset of urticarial rash, fever, and arthralgia occurs within one to two hours of exposure to relatively mild cold conditions, with these episodes typically lasting anywhere from 12 to 24 hours.⁵ MWS patients have many of the same symptoms seen in FCAS, but they tend to be more chronic and are caused by other, unknown triggers. In addition, patients with MWS may develop hearing loss, beginning in childhood. Many become completely deaf in adulthood. Reactive amyloid A amyloidosis is also seen in MWS patients, and less commonly in FCAS. Whereas inflammatory signs tend to be intermittent in FCAS and MWS, patients with NOMID experience more continuous inflammation.⁶ In addition to the rash developing shortly after birth, severe inflammation of the central nervous system – including chronic aseptic meningitis and cognitive and motor deficits – may arise later.⁵ Moreover, joint symptoms are more severe in NOMID patients, particularly in the knees, as they may become significantly enlarged due to abnormal bone and cartilage growth.

Pathogenesis of Cryopyrin-associated Periodic Syndromes
Auto-inflammatory syndromes are often confused with autoimmune disorders as the two share many features, such as joint, skin and eye involvement. However, the family of auto-inflammatory syndromes inclusive of CAPS forms a set of clinical diseases distinct from autoimmune disorders. Auto-inflammatory syndromes are characterised by a pathogenesis that does not require autoreactive T-lymphocytes or immunoglobulins to self-antigens, as in the case of autoimmune diseases. Rather, many auto-inflammatory syndromes are caused by abnormal regulation of cytokine signalling pathways, leading to persistent inflammation.

CAPS have been associated with heterozygous mutations, either inherited in an autosomal-dominant manner or developed spontaneously in the NLRP3 gene, although mutations have not been detected in all patients.^7–9 The NLRP3-encoded cryopyrin operates as part of a larger complex called the Nalp3 inflammasome, forming a molecular platform regulating the IL-1 pathway. Specifically, cryopyrin and other adaptor proteins bring together the molecules of the IL-1β- converting enzyme caspase 1, thereby resulting in the activation of
caspase and ultimately the processing of pro-IL-1β to its active proinflammatory mature form ¹⁰ (see Figure 2).

Various potential triggers have been proposed for this pathway, including muramyl dipeptide, adenosine triphosphate, toxins, Staphylococcus aureus or Listeria monocytogenes, bacterial RNA, viral infection/viral RNA, gout-associated or pseudo-gout-associated crystals,= and antiviral compounds. ^11–15 These suggest that cryopyrin acts as a sensor of pathogens or danger signals.

Although the exact mechanism underlying the dysregulation of the IL-1 pathway in CAPS is unclear, it appears that mutant cryopyrin results in an increase in the release of active IL-1β, consistent with disease-associated inflammatory symptoms including fever, arthralgias, and rash. Monocytes from CAPS patients also spontaneously secrete IL-1β due to spontaneous activation of caspase 1 and subsequent secretion of active IL-1β. ^16,17 Taken together, NLRP3 mutations are believed to result in a constitutively active or hyperactive form of the Nalp3 inflammasome complex that, in turn, causes activation of caspase 1 and hypersecretion of IL-1β.²