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

The importance of discovering the cause and pathogenesis of CAPS has wider implications than just the diagnosis and treatment of patients with this rare condition. Through the knowledge gained by this real-life model of the innate immune system, the role of the inflammasome and IL-1 in causing disease has led to discoveries with profound impact on common conditions. For example, gout attacks have been shown to be mediated by uric acid crystals triggering activation of the NLRP3 inflammasome.²⁶ IL-1 inhibition is effective in treating and preventing gout attacks.²⁷ Metabolic syndromes, such as type 2 diabetes, cause an increase in inflammasome activation of IL-1β, and coronary artery inflammation, as well as postmyocardial infarction damage is, at least in part, mediated via IL-1.²⁷

Figure 7: Schematic representation of the NLRP3 inflammasome and activators in healthy people (7a)and patients with CAPS (7b). An “X” means either a mutation or an inactivated pathway.

Treatment

As further proof of concept that CAPS is an IL-1-driven disease is the dramatic clinical and laboratory response to all IL-1 inhibitors studied thus far (see Table 3) with continued long-term response to therapy.^28-31 IL-1 inhibitors not only prevent IL-1β from binding to the IL-1 receptor, thus reducing cell signaling, but also decrease IL-1 production to levels in healthy subjects.³² In the controlled studies of rilonacept and canakinumab, >85% of patients (primarily Muckle-Wells phenotype) were complete responders, with the response occurring in the majority of patients within one week of starting therapy.^28,29 In the anakinra study of NOMID/CINCA, discontinuing anakinra resulted in a flare after a median of 5 days. As a result, the withdrawal phase of the study protocol was discontinued for ethical reasons after 11 of the 18 participants had been withdrawn from treatment.³⁰

click for large version

Table 3: Interleukin (IL) 1 Inhibitors Used in Treating CAPS

There are several important treatment issues in CAPS:

1. The most important issue is that existing damage is usually not reversible; thus, diagnosis and initiation of treatment need to be prior to development of damage. IL-1 inhibition improves existing hearing loss in only ~20–33% of patients and not after deafness has already occurred.¹⁴ Treatment usually prevents further hearing deterioration.
2. Bone deformities in NOMID/CINCA are not reversible.³³ Rather than being mediated by IL-1, bone overgrowth in NOMID/CINCA is mediated by osteoblast progenitor cells that form fibroblastoid tumors. These cells are stimulated by cAMP-dependent protein kinase A through activation of caspase-1 leading to over-expression of the early osteoblast factor Ets-1.³⁴ IL-1 inhibition also does not prevent formation of these deformities.³³
3. In many patients, the dose and frequency of IL-1 inhibition therapy need adjustment over time, particularly in children and in those with a more severe phenotype. Anakinra can be increased up to 8–9 mg/kg/day and canakinumab to 600 mg (in children ≤40 kg, 8 mg/kg) every four weeks.^31,33,35 Other patients may need less frequent administration of canakinumab.
4. It’s still unclear whether one type of IL-1 inhibition is better than others in treating central nervous system disease, particularly in patients with NOMID/CINCA, because it’s still not known whether there is adequate penetration of canakinumab across the blood–brain barrier to achieve adequate CNS penetration. In human and mouse experimental models, anakinra has been shown to have good brain penetration, but data are lacking for other IL-1 inhibitors.³⁶
5. It’s still unclear whether it’s necessary to use IL-1 inhibitors in patients with a pure FCAS phenotype, without a family history of hearing loss or amyloidosis. For untreated FCAS patients, close monitoring of their hearing and urinalysis (for proteinuria as a first sign of amyloidosis) is warranted.
6. Although clinical and laboratory remission is common, many patients continue to show immunologic disease activity with continued elevated innate immunity gene expression with high levels of MRP8 and 14 and IL-18.²¹

Summary

Although rare, it’s likely that CAPS is underdiagnosed, in particular the FCAS and MWS phenotypes. Greater awareness of the varied clinical manifestations spread across many medical specialties is essential for early diagnosis. Early diagnosis and treatment are essential for prevention of irreversible damage, in addition to improvement in the quality of life of these patients. The lessons taught to us by this rare disease, which is the prototype of IL-1β-driven autoinflammatory diseases, have implications on understanding the innate immune system and on the pathogenesis and, perhaps, treatment of many common conditions.