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Phenotypic and Functional Characterisation of Human B-cell Response in Pemphigus (CaReLyBP)

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ClinicalTrials.gov Identifier: NCT04117529
Recruitment Status : Recruiting
First Posted : October 7, 2019
Last Update Posted : November 6, 2019
Sponsor:
Collaborator:
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
Pemphigus is a rare autoimmune disease involving skin and mucous membranes characterized by the production of pathogenic autoantibodies directed against desmosomal transmembrane glycoproteins belonging to the cadherin family,responsible for the disruption of desmosomes leading to the acantholysis phenomenon.Two main classical subtypes of pemphigus have been individualized:pemphigus vulgaris and foliaceus,in which pathogenic autoantibodies are directed against desmoglein 3 and 1 respectively.The knowledge about B-cell populations responsible for pemphigus activity increased a lot.In pemphigus patients,B-cell population was shown to comprise auto-reactive B lymphocytes producing antibodies targeting desmogleins,directly responsible for disease activity,and regulatory B lymphocytes.After rituximab treatment,clinical activity was proved to be associated with circulating auto-antibodies high titers and an increase of auto-reactive B-cells,whereas clinical remission was associated with a change in B-cell populations,as B cell repertoire changed from oligoclonal to polyclonal when reconstituting after treatment,with an increase of immatures and transitional B-cells producing IL-10.The mechanisms leading to autoreactive B-cells appearance,the precise role of B-reg in immune tolerance and the factors triggering the imbalance between pro autoimmune and regulatory immune B-cells leading to pemphigus activity remain to be discovered.Polymorphonuclear neutrophil granulocytes(PMN) are the first responders of the immune system to threats by invading microorganisms.Since 2004, PMN were shown to produce neutrophil extracellular traps(NET),structures consisting of decondensed chromatin embedded with histones,granular and cytoplasmic proteins that trap and kill microbes.In lupus recent works demonstrated evidences that NETs components are found in immune complexes responsible for tissue inflammation and that polyclonal activation of B-cell as well as memory B-cell activation could be obtain in presence of immune complexes derived from NET.Besides lupus,other works showed evidence of NETs implication in inflammatory and auto-immune states in rheumatoid arthritis and small vessel vasculitis.The hypotheses is that B-cell activation by NET might not be restricted to autoimmune diseases of which antibodies target NETs components.The aim is to assess the effects on B-cell activation and the phenotypic changes in B-cell population from pemphigus patients after stimulation by NET.

Condition or disease Intervention/treatment Phase
Pemphigus Vulgaris Pemphigus Foliaceus Other: Blood sample Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Phenotypic and Functional Characterisation of Human B-cell Response in Pemphigus and Application to Other Auto-immune Diseases
Actual Study Start Date : October 22, 2019
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: Experimental Arm
Pemphigus or other autoimmune diseases.
Other: Blood sample
Collection of 2 blood sample : The first one at the inclusion in the study, the second one between 6 months and 9 months after the inclusion. The sample consists of 2 tubes of EthyleneDiamineTetraAcetic (EDTA) of 7 mL.




Primary Outcome Measures :
  1. Involvement of neutrophil extracellular traps (NETs) in the activation of B lymphocytes in Pemphigus [ Time Frame: 9 months after inclusion ]

    This primary outcome measure is composite. It will be verified according to the following points : Measurement of activation parameters of total, auto-reactive, and regulator B lymphocytes of patients :

    • Quantification of membrane markers for activation of B lymphocytes (CD80, CD86, CD40)
    • Quantification of the production of pro-inflammatory cytokines (IL-6, IL-8, Tumor Necrosis Factor alpha (TNF alpha), IFNγ) by total and auto-reactive B lymphocytes
    • Quantification of the total production of immunoglobulins and antibodies specific for the disease
    • Quantification of IL-10 and Tumor Growth Factor (TGF) beta production by regulatory B cells.


Secondary Outcome Measures :
  1. Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also in lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on membrane markers for activation of B lymphocytes [ Time Frame: 9 months after inclusion ]
    Quantification of membrane markers for activation of B lymphocytes (CD80, Cluster of Differentiation antigen 86 (CD86), CD40);

  2. Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on pro-inflammatory cytokines [ Time Frame: 9 months after inclusion ]
    Quantification of the production of pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha(Tumor Necrosis Factor alpha), IFNγ) by total and auto-reactive B lymphocytes

  3. Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also in lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on immunoglobulins and antibodies [ Time Frame: 9 months after inclusion ]
    Quantification of the total production of immunoglobulins and antibodies specific for the disease

  4. Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus,is also in lupus,rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on IL-10 and TGFbeta production by regulatory B cells [ Time Frame: 9 months after inclusion ]
    Quantification of IL-10 and TGFbeta production by regulatory B cells



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients man or woman
  • Patients above 18 years old
  • Patients fulfilling the diagnostic criteria for pemphigus (Lever et al, 1979), or for lupus (SLICC 2012), or for rheumatoid arthritis (ACR / EULAR 2009 criteria), or for Gougerot-Sjögren's syndrome (ACR criteria / EULAR 2016)
  • Clinically active disease, defined by the presence of erosions or cutaneo-mucous bubbles for pemphigus, a SLEDAI score> 0 for lupus, a DAS28> 0 score for rheumatoid arthritis, and an EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score> 0 for Gougerot-Sjögren's syndrome
  • Patients consenting to participate in the study
  • Patients benefiting from the national healthcare insurance

Exclusion Criteria:

  • Pregnant or lactating woman
  • Patient already treated with biotherapy
  • Patient already receiving treatment that may affect lymphocyte B populations: corticosteroid therapy> 10 mg / d or other immunosuppressant.
  • Patient whose weight and / or hemoglobin level does not allow an additional blood sample during the assessment already provided by the treatment (according to the values in Appendix 2 of the Decree of April 12, 2018, which lists the research mentioned in 2 ° of Article L. 1121-1 of the Public Health Code)
  • Person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04117529


Contacts
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Contact: Mohammed RAHAOUI, Mr +33148955977 mohammed.rahaoui@aphp.fr
Contact: Gérôme BOHELAY, Dr +33148955189 gerome.bohelay@gmail.com

Locations
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France
Pr Philippe MUSETTE - Hôpital AVICENNE Recruiting
Bobigny, France, 93000
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Principal Investigator: Philippe MUSETTE, Pr Assistance Publique - Hôpitaux de Paris

Publications:
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04117529     History of Changes
Other Study ID Numbers: APHP190199
2019-A00533-54 ( Other Identifier: ANSM - IDRCB number )
First Posted: October 7, 2019    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Pemphigus Vulgaris
Pemphigus Foliaceus
B-cell
Dermatology
Additional relevant MeSH terms:
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Pemphigus
Skin Diseases, Vesiculobullous
Skin Diseases
Autoimmune Diseases
Immune System Diseases