Circadian Rhythm Deregulation in Patients With CAPS

Condition(s) studied

Investigational drug(s) / intervention(s)

Genetic analysis of NLRP3: Blood test for genetic analysis of NLRP3

Circadian rhythm measurement: Wear a Withings Pulse HR (heart rate) actigraphic watch 24 hours a day for 1 month to define circadian rhythm

Saliva sampling: Saliva sampling for salivary melatonin determination

Questionnaire: Questionnaire to determine chronotype

AIDAI score: Disease activity score using AIDAI score (only for patients in the CAPS group) AIDAI : AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX

Blood sampling: 1. Inflammatory cytokines measurement : IL1-beta (Interleukin-1) and IL-18. 2. Molecular characterization of circadian clock signaling pathways

Study summary

Circadian rhythms are characterized by the physiology's adaptation to the alternation of day and night, enabling to adapt to the environment. These rhythms are generated by a molecular clock within each cell. At the molecular level, the circadian clock is based on a complex system of cell-autonomous transcription loops. These exert positive and negative feedback on themselves, generating cyclic transcriptional activity.

* In the main loop, the BMAL1 transcription factor links with CLOCK or NPAS2 ( (Neuronal PAS Domain Protein 2) to activate transcription of per1,2 and 3 and cryptochrome (cry1 and cry2), which in turn repress BMAL1/CLOCK1 transcriptional activity.. The BMAL1/CLOCK complex also activates transcription of numerous target genes (per and cry, Rev-erb, etc.)..
* other secondary loops refine the function of the first.

Recent studies suggest that many aspects of innate immunity are controlled by circadian rhythm through inhibition of NLRP3 inflammasome activation. Nevertheless, the regulation of the NLRP3 inflammasome by the circadian clock has yet to be elucidated. Inflammasomes are molecular platforms that control caspase-1 activation and consequently the maturation of precursors of (interleukine) IL-1β, pro-IL-18, a pro-inflammatory cytokine. Since its discovery, its functions have been widely characterized as part of the innate immune response as a sensor of pathogens and danger signals (extracellular ATP (Adenosine triphosphate), atmospheric pollutants). NLRP3 (nucleotide-binding domain LRR (leucin-rich repeat ) and pyrin-containing receptor 3) has been described for its genetic association with dominant monogenic hereditary syndromes characterized by recurrent systemic inflammatory episodes in the absence of any infection or autoimmune disease, known as CAPS (cryopyrin-associated periodic syndrome) or cryopyrinopathies which is a continuum of diseases ranging from a moderate to the most severe form of the syndrome: familial cold urticaria syndrome, Muckle-Wells syndrome (MWS), and CINCA/NOMID syndrome.

Interestingly, patients with Muckle-Wells syndrome show a circadian pattern of symptoms, with a recurrent, predominantly vesperal fever peak lasting a few hours, and extreme fatigue on a daily basis. However, a molecular link between the circadian clock and CAPS pathology remains to be determined.

The aim of this protocol is to identify circadian rhythm dysregulation in patients with CAPS confirmed by genetic analysis of NLRP3, to demonstrate a link between circadian clock and CAPS syndrome, and to identify circadian clock regulatory pathways.

Eligibility

Primary outcome measure(s)

• Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3, — 6 months after inclusion
  Concentration of the peak secretion of melatonin in both arms
• Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3, — 12 months after inclusion
  Concentration of the peak secretion of melatonin in both arms
• Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3, — 6 months after inclusion
  time of the peak secretion of melatonin in both arms
• Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3, — 12 months after inclusion
  time of the peak secretion of melatonin in both arms

Trial sites (6)

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