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

August 1, 2017 updated by: Raashid Luqmani, University of Oxford

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).

Study Overview

Status

Unknown

Conditions

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.

Study Type

Observational

Enrollment (Anticipated)

85

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Oxford, United Kingdom, OX3 7HE
        • Recruiting
        • Oxford University Hospitals NHS Foundation Trust
        • Contact:
          • Jana Vaskova
        • Principal Investigator:
          • Raashid Luqmani, DM FRCP FRCPE

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Within one month of diagnosis (or flare of vasculitis)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
Within one month of diagnosis (or flare of vasculitis)
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)
Within one month of diagnosis (or flare of vasculitis)
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
Within one month of diagnosis (or flare of vasculitis)
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.
Within one month of diagnosis (or flare of vasculitis)
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.
Within one month of diagnosis (or flare of vasculitis)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

Arthritis Research UK

Investigators

  • Principal Investigator: Raashid A Luqmani, DM FRCP, Professor of Rheumatology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2015

Primary Completion (Anticipated)

August 1, 2018

Study Completion (Anticipated)

December 1, 2018

Study Registration Dates

First Submitted

July 10, 2015

First Submitted That Met QC Criteria

July 14, 2015

First Posted (Estimate)

July 15, 2015

Study Record Updates

Last Update Posted (Actual)

August 2, 2017

Last Update Submitted That Met QC Criteria

August 1, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20892

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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