Clinical trial NCT04902807: Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
Official title: Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Autoimmune Lymphoproliferative Syndrome
Autoimmune Cytopenia
Autoimmune Diseases
Autoimmune Anemia
Autoimmune Thrombocytopenia
Autoimmune Hepatitis
Autoimmune Diabetes
Autoimmune Rheumatologic Disease
Systemic Lupus Erythematosus
Juvenile Idiopathic Arthritis
Hemophagocytic Lymphohistiocytoses
EBV Lymphoproliferation
RAS-Associated Autoimmune Leucoproliferative Disease
Primary Immunodeficiency
APECED
IPEX
BENTA
Enteropathy, Autoimmune
Combined Immunodeficiency
IBD
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2021-05-26
Enrollment: 500
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with PIDs and autoimmunity/inflammation related to known and unknown genetic defects (ALPS, Cytopenia, Enteropathy-IBD, pSLE, JIA, FHL, CA-EBV, CID) and their healthy relatives (controls) will be recruited in 2 clinical services of Necker hospital: Paediatric Rhumatology Immuno Hematology department Department, and paediatric Paediatric Gastroenterology department Department.

Unrelated controls will be recruited in the Paediatric Rhumatology Immuno Hematology Department, the Paediatric Gastroenterology Department,also be recruited in the Department of Paediatric Visceral and Urologic Surgery and the Department of Maxillofacial Surgery and Paediatric Plastic Surgery within patients hospitalised for a surgery and not affected by an immune-related disease or a cancer.

Brief summary: The main objective of this study is to generate diagnosis and therapeutic-decision tools through the identification of molecular causes of PIDs with autoimmunity/inflammation and the variability in disease outcome at the transcriptional level using a combination of omics signatures (transcriptomics, epigenomics, proteomics, metagenomics, metabolomics and lipidomics).

Detailed description: Primary Immune deficiencies (PIDs) are a group of monogenic diseases related to developmental or functional dysfunction of one or several immune cell types. Individually there are rare entities, but collectively they group several thousands of patients.

Approximately 500 000 patients suffer from PIDs worldwide, making their management a true health-care concern. According to European Society for Immunodeficiencies (ESID), the age group in which PIDs is most frequently diagnosed is under 19 years of age (62%)1. PIDs are causing susceptibility to severe and life-threatening infections by common pathogens, but they also predispose to cancer and can initially manifest as autoimmune and inflammatory diseases.

Multiple mechanisms underlie the development of autoimmunity/inflammation in PIDs. Moreover, their development can be influenced by the composition of the microbiota, which shapes host metabolic and immune functions and can be modified by many environmental factors. In the last two decades a particular emphasis was given to the elucidation of the genomic mutations causing PIDs. This led to a burst of genetic diagnosis as the numbers of known monogenic causes of PIDs rose from around 200 in 2010 to more than 310 in 2017. These genomic approaches revealed that: 1) a given monogenic defect can lead to very dissimilar clinical presentations, disproving the initial concept that a monogenic defect is associated with specific clinical manifestations ; and 2) the number of cases of autosomal dominant genetic deficiencies has increased, with sometimes a partial clinical penetrance so that some relatives carrying the causal genetic variant remain asymptomatic. Hence, onset and presentation of autoimmune and inflammatory diseases in PIDs is highly unpredictable.

PIDs with autoimmunity/inflammation usually require life-long symptomatic treatments including broad immunosuppression or immunotherapies. On the long term, such treatments can have important side effects or poor efficacy and they result in high burden cost. It is therefore crucial to diagnose PIDs as early as possible in order to select the most efficient therapy based not only on clinical features as it is nowadays, but to include the underlying molecular cause of immune dysregulation.

The central goal of this project is to explain the very variable outcome of monogenic autoimmune and inflammatory diseases and to define predictive biomarkers in order to stratify patients and to optimize therapeutic choices.

Eligibility criteria: Inclusion Criteria for controls (patients relatives and unrelated subjects):

* Individuals aged\<18 y/o.
* Individuals \> 6 kg
* Individuals not affected by an immune-related disease or not affected by cancer
* Individuals whose parents have signed an enlightened consent.

Inclusion criteria for patients

* Individuals with health insurance.
* Patients treated at Necker hospital with PIDs and autoimmunity/inflammation related to known genetic defects (cytopenia, Enteropathy Inflammatory bowel disease (IBD), Systemic Lupus Erythematosus (SLE), Juvenile Idiopathic Arthritis (JIA), Familial Hemophagocytic Lymphohistiocytosis (FHL), chronic EBV infection associated (Ca-EBV) with EBV-infected T and/or Natural Killer (NK) cells and with a high risk to develop macrophage activation syndrome similar to FHL. See table below for diagnosis inclusion criteria.
* Individuals aged\<18 y/o.
* Individuals \> 9 kg
* Patients whose parents have signed an enlightened consent.

Exclusion Criteria:

* Intake of antibiotics within 2 weeks prior inclusion
* Absence of parent's or child consent form
* Cytotoxic cancer treatments
* antiviral treatments (HIV, hepatitis ...)
* Short term life-threatening conditions
* Individuals placed under judicial protection

Primary outcomes:
measure: Generate a diagnosis and therapeutic-decision tools
timeFrame: 5 years
Secondary outcomes:
measure: 1- Development of an atlas of molecular interactions leading to autoimmunity and inflammation
timeFrame: 5 years
measure: 2 - To develop an artificial intelligent online application
timeFrame: 5 years
measure: 3- Ancillary study (pilot study)
timeFrame: 5 years
Other outcomes:
Locations:
Study officials:
affiliation: Institut Imagine
name: Frédéric Rieux-Laucat
role: PRINCIPAL_INVESTIGATOR
References: