Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Interferon-lambda: Novel Biologics for Controlling Neutrophil-mediated Pathology in Rheumatic Diseases? (ILAND)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02498808
Recruitment Status : Recruiting
First Posted : July 15, 2015
Last Update Posted : August 2, 2017
Sponsor:
Collaborator:
Arthritis Research UK
Information provided by (Responsible Party):
Raashid Luqmani, University of Oxford

Brief Summary:

Neutrophils emerge as key immune cells in the initiation and perpetuation of immune responses in autoimmune diseases. They display marked abnormalities in phenotype and function in various autoimmune diseases, including systemic vasculitis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

These neutrophils are characterised by an extended life span, increased capacity to produce reactive oxygen species, active gene expression and release of extracellular traps. Consequently, there is a need for better understanding of neutrophil phenotype and functions in these conditions, as well as for identifying molecules capable of specifically manipulating neutrophil function. The investigators have recently discovered that interferon lambdas (IFN-λs), also known as interleukin 28 (IL28) and interleukin 29 (IL29), class II cytokines with previously studied anti-viral biological functions, specifically suppress neutrophil infiltration and interleukin-1β production and thereby, halt and reverse the development of collagen induced arthritis (CIA). The investigators propose to further investigate the cellular and molecular mechanisms behind this suppression and examine the translational potential of the investigators' finding by examining the IFN-λ receptor expression and function in neutrophils isolated from the blood of healthy donors and rheumatic patients (early rheumatoid arthritis and vasculitis).


Condition or disease
Arthritis Vasculitis

Detailed Description:

Expression of Interferon lambda receptor 1 (IFNLR1)/interleukin 28 Receptor Alpha (IL28RA) in human neutrophils.

Neutrophils will be isolated from freshly drawn human blood with subsequent removal of red blood cells with dextran and/or magnetic-activated cell sorting (MACS). The investigators' preliminary results show that neutrophils isolated from the blood of a healthy donor express higher level of IL28RA messenger Ribonucleic Acid (mRNA) compared to Cluster of Differentiation-14 (CD14) negative or CD14 positive lymphocytes. To better understand the relative spread of IL28RA mRNA levels due to human heterogeneity, the investigators will compare the levels of IL28RA expression in neutrophils isolated from blood of 20 healthy donors. The investigators will examine whether treatment of human neutrophils ex vivo with recombinant human IL29 (Bristol- Meyers Squibb, BMS) induces Signal Transducer and Activators of Transcription 1 (STAT1) signalling. The investigators will also test newly generated antibodies to human IL28RA which have shown some specificity in IL28RA detection in cell lines, on neutrophil isolated from blood.

Expression of IFNLR1/IL28RA in neutrophils isolated from blood of rheumatic patients.

The investigators will then compare the levels of IL28RA expression on neutrophils isolated from blood of (1) 15 patients in the early phases of rheumatoid arthritis (RA) and while naïve to biologic therapeutic intervention; (2) 15 vasculitis patients with giant cell arteritis (GCA) (within one week of commencing high dose glucocorticoid) and (3) 15 vasculitis patients with granulomatosis with polyangitis (GPA; Wegener's) at presentation or during a relapse, prior to initiation of immunosuppressive therapy with either cyclophosphamide or rituximab. All patients will undergo standardised assessment of disease activity and damage, i.e. the Birmingham Vasculitis Activity Score version 3.0 (BVAS 3.0) and the Vasculitis Damage Index version 1.0 (VDI) for vasculitis or the disease activity score for 28 joints (DAS-28) for RA. This will allow the investigators to predict whether rheumatic patients are likely to respond to IL29 treatment.

Functional characterisation of human neutrophils treated with IL29.

The investigators will conduct a selective evaluation of the expression of adhesion molecules, the migratory responses and functional properties of human neutrophils treated with IL29 ex vivo. These selected activities will be examined in the IL29 treated neutrophils from blood of healthy donors, with or without stimulation with lipopolysaccharide (LPS), phorbol myristate acetate (PMA) or serum from RA and vasculitis patients. The investigators will assess the impact of IL29 treatment on neutrophils isolated from the blood of patients with RA and vasculitis.


Layout table for study information
Study Type : Observational
Estimated Enrollment : 85 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Interferon-lambda: Novel Biologics for Controlling Neutrophil-mediated Pathology in Rheumatic Diseases?
Actual Study Start Date : September 2015
Estimated Primary Completion Date : August 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Arthritis Vasculitis
Drug Information available for: Interferon

Group/Cohort
Healthy controls
Staff or patients attending hospital or visitors attending with patients. They should not have vasculitis or inflammatory arthritis
Early rheumatoid arthritis
Newly diagnosed patients with rheumatoid arthritis attending hospital, prior to use of biologic therapies
New or relapsing ANCA vasculitis
Newly diagnosed or flaring patients with anti-neutrophil cytoplasm antibody associated systemic vasculitis attending hospital
Newly diagnosed giant cell arteritis
Newly diagnosed patients with giant cell arteritis attending hospital



Primary Outcome Measures :
  1. Expression of IFNLR1/IL28Ra in human neutrophils, by laboratory measurement of blood neutrophils [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be tested on samples of blood taken from patients


Secondary Outcome Measures :
  1. Vasculitis disease activity, based on a scale of disease activity in vasculitis (Birmingham Vasculitis Activity Score version 3.0, BVAS 3.0) [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be assessed using the patient using the Birmingham Vasculitis Activity Score (version 3.0), a questionnaire completed by the clinician. A numeric score can be calculated (range 0-63)

  2. Vasculitis damage, based on a scale of disease damage in vasculitis (Vasculitis Damage Index version 1.0, VDI 1.0) [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be assessed using the Vasculitis Damage Index (Version 1.0), a questionnaire completed by the clinician. A numeric score can be calculated (0-64)

  3. Disease activity assessment score for arthritis, based on a scale (Disease activity score for 28 joints, DAS-28) [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be assessed using a score of the number of painful and tender joints, results of the test of inflammatory markers (usually the C-reactive protein) and a patient's estimate of disease on a visual analogue scale. The data is recorded in a specifically designed calculator, providing a numerical score from 0 to 10

  4. Expression of Toll like receptors, adhesion molecules and chemokine receptors in human neutrophils, by laboratory measurement of blood neutrophils [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be tested on samples of blood taken from patients.

  5. STAT1 signalling by neutrophils [ Time Frame: Within one month of diagnosis (or flare of vasculitis) ]
    This will be tested on samples of blood taken from patients.


Biospecimen Retention:   Samples With DNA
Blood samples


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Healthy volunteers will be recruited as staff or patients attending secondary care or accompanying patients but who do not have vasculitis or any form of inflammatory arthritis Patients with vasculitis or arthritis who are attending secondary care will be invited to participate if they fulfill eligibility criteria.
Criteria

Inclusion Criteria:

  • Healthy volunteer or
  • Recent diagnosis of rheumatoid arthritis within 1 month or
  • New diagnosis of giant cell arteritis within 1 month or
  • New diagnosis of anti-neutrophil cytoplasm antibody associated vasculitis within 1 month or
  • Flare of anti-neutrophil cytoplasm antibody associated vasculitis within one month

Exclusion Criteria:

  • Unable to provide written informed consent

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): NCT02498808


Contacts
Layout table for location contacts
Contact: Raashid A Luqmani, DM FRCP 01865227971 jana.vaskova@ndorms.ox.ac.uk
Contact: Jana Vaskova 01865227971 jana.vaskova@ndorms.ox.ac.uk

Locations
Layout table for location information
United Kingdom
Oxford University Hospitals NHS Foundation Trust Recruiting
Oxford, United Kingdom, OX3 7HE
Contact: Jana Vaskova         
Principal Investigator: Raashid Luqmani, DM FRCP FRCPE         
Sponsors and Collaborators
University of Oxford
Arthritis Research UK
Investigators
Layout table for investigator information
Principal Investigator: Raashid A Luqmani, DM FRCP Professor of Rheumatology

Publications:
Layout table for additonal information
Responsible Party: Raashid Luqmani, Professor of Rheumatology, University of Oxford
ClinicalTrials.gov Identifier: NCT02498808     History of Changes
Other Study ID Numbers: 20892
First Posted: July 15, 2015    Key Record Dates
Last Update Posted: August 2, 2017
Last Verified: August 2017

Keywords provided by Raashid Luqmani, University of Oxford:
Interferon lambda
Interleukin-29
Neutrophil

Additional relevant MeSH terms:
Layout table for MeSH terms
Vasculitis
Rheumatic Diseases
Collagen Diseases
Vascular Diseases
Cardiovascular Diseases
Musculoskeletal Diseases
Connective Tissue Diseases
Interferons
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents