Cryopyrin-Associated Periodic Syndromes: Difficult to Recognize, Diagnose, Treat

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Table 2: Proposed Clinical Diagnosis of CAPS for Treatment Eligibility in the Absence of Genetic Confirmation

Pathogenesis

The discovery of CAPS, the mutation in the NLRP3 gene and the role of cryopyrin in the production and activity of IL-1β serve as a human laboratory that has led to a wider understanding of the innate immune system, especially that of the inflammasome and pro-inflammatory cytokines. CAPS is the prototype of IL-1β-driven autoinflammatory diseases.

Inflammasomes are intracellular molecular complexes that respond to both external and internal agents to activate cytokines IL-1β and IL-18 (see Figures 7a and b). In health, the inflammasome is activated by many exogenous triggers, such as pathogens (via pathogen-associated molecular pattern molecules [PAMPs]) or damage-associated molecular pattern molecules (DAMPs), such as crystals (urates in gout) or cholesterol (atherosclerosis). In addition, adenosine triphosphate (ATP), as a second activating signal, is usually necessary to activate the inflammasome via an efflux of cellular potassium.18 PAMPs and DAMPs act through membrane-based, toll-like receptors and other signals, and lead to the assembly of several proteins (many with a pyrin domain), one of which is the NLRP3 inflammasome. The inflammasome activates caspase 1, which converts pro-IL-1β to active IL-1β. Other important regulators of the inflammasome are the level of intracellcular calcium (increases activity) and cyclic adenosine monophosphate (cAMP, decreases activity).¹⁹

In patients with NLRP3 mutations, which lead to cryopyrin gain of function, many of these stages are bypassed, augmented or diminished, with the net result being increased spontaneous activation of the inflammasome. In CAPS, the second signal of ATP is not necessary for activation of the inflammasome.²⁰ In patients with CAPS, the inflammasome may be more sensitive to the calcium-sensing receptor (CASR), resulting in increased release of calcium from the endoplasmic reticulum via phospholipase C, which catalyzes inositol-1,4,5-trisphosphate production and, thereby, induces release of calcium. This leads to further spontaneous assembly and activation of the inflammasome.19 In CAPS, the binding affinity of cAMP to the mutated inflammasome is decreased, thus reducing the regulatory effect of cAMP on its activity.¹⁹

Figure 6: Axial T1-weighted sequence postgadolinium demonstrates symmetric abnormal enhancement in the fundus of the internal acoustic canal. Courtesy Dr. Helen Branson, The Hospital for Sick Children.

In addition to IL-1β, other cytokines and even the adaptive immune system may contribute to inflammation in CAPS patients, although the effectiveness of treatment with IL-1 inhibitors points toward the predominance (or perhaps upstream) effect of IL-1 in CAPS. IL-17 production is induced in CAPS patients by IL-1, resulting in increased TH-17 cells in CAPS patients.²¹ These effects are reversed by IL-1β inhibition. IL-18 is markedly increased in CAPS patients. In mouse models of CAPS, IL-18 appears to play an important role in the early phase of disease.²² In these models, IL-1 inhibition may not result in clinical improvement in young mice. Hence, in the rare patient who does not respond well to IL-1 inhibition, particularly at a very early age, IL-18 may play a more important role in the pathogenesis of disease. Evidence for phagocyte activation in CAPS patients is shown by elevated levels of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 in untreated patients, with a marked decrease (although not always to normal levels) with IL-1 inhibitor treatment.²³ Oxidative stress of monocytes has been shown to lead to a decrease in IL-6 and IL-1 receptor antagonist in CAPS patients, exacerbating IL-1 overproduction.²⁴ Defective cell death mechanism related to cryopyrin mutations has been shown to be associated with tissue infiltration of neutrophils.²⁵