Circadian Rhythm Deregulation in Patients With CAPS

Not Applicable

Not yet recruiting

• Conditions: CINCA Syndrome; Cryopyrin Associated Periodic Syndrome; Familial Cold Urticaria; Muckle-Wells Syndrome
• Interventions: Genetic: Genetic analysis of NLRP3; Device: Circadian rhythm measurement; Biological: Saliva sampling; Other: Questionnaire; Biological: Blood sampling; Other: AIDAI score

• Registration Number: NCT06544018
• Lead Sponsor: Hospices Civils de Lyon

Brief 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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-05
• Study First Submitted: 2024-05-07
• Study First Submitted QC: 2024-08-06
• Last Update Submitted: 2024-08-06
• Study First Posted: 2024-08-09
• Last Update Posted: 2024-08-09
• Study Start: 2024-09-01
• Primary Completion: 2027-09-01
• Study Completion: 2027-11-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Patient with CAPS group :

• Patients aged 6 and over
• Participant with CAPS confirmed by NLRP3 genetic analysis
• Weight greater than or equal to 25 Kg
• Parents/guardians who have been informed of the study and have signed a consent form.
• Patient affiliated to a social security scheme

Control group (healthy participant):

• Participant aged 6 and over

• Weight greater than or equal to 25 Kg

• Participant living in the same household as a subject with CAPS genetically confirmed by NLRP3 analysis and included in the protocol

• Participant with no CAPS (a priori) who consents to NLRP3 genetic analysis

• Parents/guardians who have been informed of the study and have signed a consent form.

• Participant who has been informed of the study and has agreed to take part

• Participant affiliated to a social security scheme

  • Exclusion Criteria :

Patient with CAPS group :

• Patients with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin).
• Patients with sleep apnea syndrome
• Patients working regular night shifts or alternating day and night shifts
• Pregnant or breast-feeding women
• Parents with an infant under 6 months of age
• Patient participating in another interventional drug study
• Deprivation of civil rights (curators, guardianship, safeguard of justice)

Control group (healthy participant):

• Participants with a chronic illness (ALD beneficiaries)
• Participants with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin)
• Participants working regular night shifts or alternating day and night shifts
• Pregnant or breast-feeding women
• Parents with an infant under 6 months of age
• Participant participating in another interventional drug study
• Deprivation of civil rights (curators, guardianship, safeguard of justice)

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control group	Blood sampling	Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol
Patients with cryopyrin-associated periodic syndrome (CAPS)	Blood sampling	Confirmed by genetic analysis of NLRP3
Control group	Genetic analysis of NLRP3	Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol
Patients with cryopyrin-associated periodic syndrome (CAPS)	Genetic analysis of NLRP3	Confirmed by genetic analysis of NLRP3
Patients with cryopyrin-associated periodic syndrome (CAPS)	Saliva sampling	Confirmed by genetic analysis of NLRP3
Control group	Circadian rhythm measurement	Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol
Control group	Saliva sampling	Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol
Patients with cryopyrin-associated periodic syndrome (CAPS)	Circadian rhythm measurement	Confirmed by genetic analysis of NLRP3
Patients with cryopyrin-associated periodic syndrome (CAPS)	Questionnaire	Confirmed by genetic analysis of NLRP3
Patients with cryopyrin-associated periodic syndrome (CAPS)	AIDAI score	Confirmed by genetic analysis of NLRP3
Control group	Questionnaire	Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol

Primary Outcome Measures

Name	Time	Method
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

Secondary Outcome Measures

Name	Time	Method
Comparison of inflammatory state	12 months after inclusion	basal levels of IL18 in patient monocytes in both arms
Chronotype determination	6 th month	Number of patients in each chronotype for the 2 arms based on the specific questionnaire in both arm
number of steps	6 th month	Daily activity in both arms
Disease activity measurement	12 months after inclusion	Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score \>9 in CAPS patient arm
sleep duration	6 th month	sleep duration in both arms
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.	6 th month	Determination of circadian rhythms : phase in both arms
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared control arm	6 months after inclusion	Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms
presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm	12 months after inclusion	Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms
presence or absence of ASC inflammasome protein regulatory pathway in CAPS arm compared to control arm	12 months after inclusion	Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared to control arm	12 months after inclusion	Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms
presence or absence of ASC inflammasome protein regulatory pathway in CAPs arm compared to control arm	6 months after inclusion	Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms
presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm	12 months after inclusion	Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms

Trial Locations

Locations (6)

Hôpital Claude Huriez (CHU de Lille); 🇫🇷 Lille, France

Hôpital Femme-Mère-Enfant (HCL); 🇫🇷 Bron, France

Hôpital Tenon (AP-HP); 🇫🇷 Paris, France

Hôpital Edouard Herriot (HCL); 🇫🇷 Lyon, France

Hôpital Kremlin-Bicêtre (AP-HP); 🇫🇷 Paris, France

Hôpital de la Croix-Rousse (HCL); 🇫🇷 Lyon, France